The mechanisms responsible for the accumulation of Aβ plaques and neurofibrillary tangles, composed of phosphorylated Tau protein, in Alzheimer's disease (AD) remain a mystery. Dysfunction of the ubiquitin-proteasome system (UPS) largely contributes to abnormal protein aggregation. A cascade of ubiquitinating enzymes promotes protein ubiquitination, while deubiquitylases (DUBs) regulate its reversal. Disruptions in ubiquitination and deubiquitination processes result in abnormal protein aggregation and the formation of inclusion bodies, ultimately leading to neuronal damage. Recent studies have highlighted the significant role of protein ubiquitination and deubiquitination in the pathogenesis of AD. E3 ubiquitin ligases, which facilitate protein ubiquitination, are beneficial for Aβ clearance, synaptic function, gap junction maintenance, mitophagy, and neuroinflammation. Conversely, DUBs, responsible for removing ubiquitin from substrate proteins, inhibit Aβ and Tau degradation while promoting neuroinflammation in neurons. This review provides a thorough overview of the involvement of E3 ubiquitin ligases and DUBs in AD, highlighting their diverse roles in aspects of pathophysiological processes.

Japanese encephalitis is a neurological disease caused by the mosquito-borne Japanese encephalitis virus (JEV). The clinically approved antiviral drugs for JEV infection are not available. In our present study, we investigated the antiviral activity of garlic oil and its key organosulfur compounds against JEV. The garlic oil showed anti-JEV activity in Neuro-2a cells at a 20 μg/ml concentration. Further, the components of garlic oil, i.e., diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), were screened for their anti-JEV activity. DATS was active among these compounds and displayed higher antiviral activity against JEV than DAS and DADS. Moreover, DATS inhibited JEV replication in a dose- and time-dependent manner. Mechanistic investigations revealed the activation of mTOR signaling associated protein levels (phospho-mTOR, mTOR, phospho-AKT, AKT) and phospho-p62 autophagy marker in JEV-infected Neuro-2a cells after 48 h post-treatment with DATS. These results demonstrate that DATS inhibits JEV replication by suppressing autophagy via mTOR-dependent pathway.

Background: Glutathione peroxidase 4 (GPX4), an important factor regulating redox homeostasis, plays an important role in tumor microenvironment and progression. However, the role of GPX4 in gastric cancer (GC) is unclear. Methods: Spectral flow cytometry and multiplex immunohistochemistry were employed to assess the correlation between GPX4 expression and immune cell infiltration. Metabolomics analysis of conditioned media from GPX4 knockdown NUGC3 cells identified metabolic alterations. Additionally, both in vitro and in vivo functional studies were conducted to elucidate the mechanistic role of GPX4 in regulating the tumor microenvironment and progression. Results: Knockdown of GPX4 in GC cells inhibited tumor growth, enhanced CD8+ T cell infiltration, and suppressed the polarization of tumor-associated macrophages (TAMs) toward the pro-tumor M2 phenotype. Multiplex immunohistochemistry revealed a positive correlation between GPX4 expression and M2 macrophage infiltration in clinical samples from patients with GC. Metabolomics revealed that GPX4 knockdown regulate kynurenine metabolism pathway. Furthermore, mechanistic studies reveal that GPX4 silencing elevates lipid peroxidation, triggering the conversion of KYNU ubiquitin chain modifications from K48 to K63. Such ubiquitination remodeling stabilizes KYNU expression (a key kynurenine-metabolizing enzyme), reduces kynurenine accumulation, and ultimately reprograms TAM polarization to enhance antitumor immunity. We also identified that the K96 and K163 sites are important for KYNU's modification by K48 and K63 ubiquitin chains. Conclusion: Our study not only affirm the role of GPx4 in GC progression but also highlight it as a promising target for reshaping the immune microenvironment.

Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation and recycling. In Caenorhabditis elegans, autophagy participates in diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, and adaptive immunity. Genetic screens in C. elegans have identified a set of metazoan-specific autophagy genes that form the basis for our molecular understanding of steps unique to the autophagy pathway in multicellular organisms. Suppressor screens have uncovered multiple mechanisms that modulate autophagy activity under physiological conditions. C. elegans also provides a model to investigate how autophagy activity is coordinately controlled at an organismal level. In this chapter, we will discuss the molecular machinery, regulation, and physiological functions of autophagy, and also methods utilized for monitoring autophagy during C. elegans development.

Autophagy-dependent cell death (ADCD) is a context-specific form of programmed cell death that plays an important role in development and homeostasis. During Drosophila metamorphosis, hormonal cues modulate growth and other signalling cascades which results in autophagy-dependent degradation of the obsolete larval midgut. While this process does not require caspase activity or apoptotic machinery, several canonical autophagy-related proteins are also dispensable, suggesting additional regulators may be involved in effectively eliminating the larval midgut. Ubiquitination, a process that attaches one or more ubiquitin moieties to a substrate through sequential reactions involving a cascade of enzymes, plays a critical role in autophagy. As the specific role(s) of ubiquitination in ADCD has not been explored, we previously performed a RNAi-mediated knockdown screen of over 250 ubiquitin machinery genes in GFP-labelled Drosophila larval midguts and identified 18 candidate regulators of midgut degradation. In this work, we screened candidate genes for a role in autophagy-dependent midgut degradation by analysing mosaic clones and genetic interactions with Atg1. Validation and further studies into the ubiquitin conjugating enzyme, Effete (Eff), and two ubiquitin ligases, Cullin-4 (Cul4) and Supernumerary limbs (Slmb), demonstrated interplay between ubiquitination and the autophagy machinery in coordinating autophagy-dependent midgut degradation.

Autophagy is a conserved catabolic process that removes protein clumps and defective organelles, thereby promoting cell equilibrium. Growing data suggest that dysregulation of the autophagic pathway is linked to several cancer hallmarks. Long non-coding RNAs (lncRNAs), which are key parts of gene transcription, are increasingly recognized for their significant roles in various biological processes. Recent studies have uncovered a strong connection between the mutational landscape and altered expression of lncRNAs in the tumor formation and development, including leukemia. Research over the past few years has emphasized the role of lncRNAs as important regulators of autophagy-related gene expression. These RNAs can influence key leukemia characteristics, such as apoptosis, proliferation, epithelial-mesenchymal transition (EMT), migration, and angiogenesis, by modulating autophagy-associated signaling pathways. With altered lncRNA expression observed in leukemia cells and tissues, they hold promise as diagnostic biomarkers and therapeutic targets. The current review focuses on the regulatory function of lncRNAs in autophagy and their involvement in leukemia, potentially uncovering valuable therapeutic targets for leukemia treatment.

The Rab40 subfamily of proteins consists of unique small monomeric GTPases that form CRL5-based ubiquitin E3 ligase complexes and regulate ubiquitylation of specific target proteins. Recent studies have shown that Rab40 proteins play an important role in regulating cell migration, but the underlying mechanisms of how the Rab40-CRL5 complex functions are still not fully understood. In this study, we identified AMBRA1 as a novel binding partner of Rab40 GTPases and show that this interaction mediates a bidirectional crosstalk between the CRL4 and CRL5 E3 ligases. Importantly, we found that Rab40-CRL5 ubiquitylates AMBRA1, which does not result in AMBRA1 degradation but, instead, appears to induce AMBRA1-dependent regulation of gene transcription. The global transcriptional profiles identified by RNA sequencing showed that AMBRA1 regulates transcription of genes related to cell adhesion and migration. Additionally, we show that AMBRA1-dependent transcription regulation does not require the enzymatic activity of AMBRA1-CRL4, and that Rab40-induced AMBRA1 ubiquitylation leads to dissociation of the AMBRA1-CRL4 complex. Taken together, our findings reveal a novel function of the Rab40-CRL5 complex as an important regulator of AMBRA1-dependent transcription of genes involved in cell migration.

Chemotherapy remains the primary treatment for unresectable or advanced postoperative colorectal cancers. However, its effectiveness is compromised by chemoresistance, which adversely affects patient outcomes. Dysregulated macroautophagy/autophagy is a proposed mechanism behind this resistance, with ubiquitination playing a key regulatory role. In this study, we identify the transcription factor HMBOX1 (homeobox containing 1) as a critical regulator of chemoresistance in colorectal cancer. RNA sequencing revealed that HMBOX1 is downregulated in drug-resistant colorectal cancer cells and tissues, with its low expression linked to poor prognosis. An integrated analysis of genes associated with autophagy and 5-fluorouracil (5-FU) resistance was conducted, verified in the colorectal cancer tissues of patients by single-cell RNA sequencing and immunostaining. Mass-spectrometry-based proteomics and RNA sequencing were used to elucidate the underlying molecular mechanisms. Functionally, upregulation of HMBOX1 enhances the sensitivity of colorectal cancer cells to the first-line treatment with 5-FU by inhibiting autophagy. Mechanistically, HMBOX1 promotes the transcription of the E3 ubiquitin ligase HACE1, which in turn enhances ATG5 K63-ubiquitination and subsequent proteasome-mediated degradation. This results in decreased ATG5 levels, inhibiting autophagy and thus reducing 5-FU resistance in colorectal cancer cells both in vitro and in vivo. Furthermore, we confirm that HMBOX1 expression positively correlates with HACE1 expression and inversely correlates with autophagy levels in clinical colorectal cancer tissues. Our findings suggest that HMBOX1 downregulation drives 5-FU resistance through autophagy enhancement in colorectal cancer, highlighting HMBOX1 as a potential target for improving chemosensitivity and patient prognosis.Abbreviation: 3-MA: 3-methyladenine; 5-FU: 5-fluorouracil; ATG: autophagy related; CASP3: caspase 3; C-CASP3: cleaved caspase 3; C-PARP: cleaved PARP; CCK8: cell counting kit-8; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CNV: copy number variation; co-IP: co-immunoprecipitation; COAD: colorectal adenocarcinoma; CQ: chloroquine; CRC: colorectal cancer; CR: complete response; FHC: fetal human colon; GEO: Gene Expression Omnibus; HACE1: HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1; HMBOX1: homeobox containing 1; IHC: immunohistochemistry; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mIHC: multiplexed immunohistochemistry; MUT: mutant; NC: negative control; OS: overall survival; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PFS: progression-free survival; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TF: translation factor; USP22: ubiquitin specific peptidase 22; WT: wild type.

Among the genomic alterations identified as risk factors in mice models of autism spectrum disorders (ASD), heterozygous deletion of Ambra1 (Activating Molecule in Beclin1-Regulated Autophagy) triggers an ASD phenotype associated with hippocampal hyperexcitability exclusively in the female sex although Ambra1 protein is comparably expressed in the hippocampus of symptomatic females and asymptomatic males. Given the intricate relationship between Ambra1 deficiency and sex in the etiology of ASD, we took advantage of asymptomatic mice including Ambra1+/- males and wild-type (Wt) mice of both sexes to investigate whether their non-pathogenic variations in Ambra1 levels could underlie a differential susceptibility to exhibit ASD-like traits in response to experimental elevation of hippocampal excitability. Here we report that selective activation of inhibitory DREADD in CA1 parvalbumin-positive interneurons (PV-IN) reduces GABAergic currents onto pyramidal neurons (PN), causes social and attentional deficits, and augments the proportion of immature/thin spines in CA1 PN dendrites to the same extent in Ambra1+/- males and Wt mice of both sexes. Our findings show that the substantial hippocampal variations in pro-autophagic Ambra1 gene product shown by asymptomatic mice differing in mutation and/or sex do not underlie a differential reactivity to chemogenetic induction of idiopathic ASD.

Accumulation of free α-globin is a critical factor in the pathogenesis of β-thalassemia. Autophagy plays a crucial role in clearing toxic free α-globin, thereby reducing disease severity. However, the impact of natural mutations in autophagy-related genes (ATGs) on the phenotypic variability of β-thalassemia remains unclear. In this study, we systematically investigated the relationship between variants in ATGs and disease phenotypes in a cohort of 1022 patients with β-thalassemia, identifying 4 missense mutations in the autophagy and beclin 1 regulator 1 (AMBRA1) gene. Disruption of the Ambra1 gene in β-thalassemic mice was found to reduce autophagic clearance of α-globin in red blood cell precursors, exacerbating disease phenotypes. Functional characterization of the AMBRA1 gene and these mutations in patient-derived CD34+ cells, edited human umbilical cord blood-derived erythroid progenitor 2 (HUDEP-2) cells, and engineered HUDEP-2 β-thalassemic cells confirmed that AMBRA1 facilitates the autophagic clearance of free α-globin in human erythroid cells. Functional studies demonstrated that AMBRA1 missense mutants destabilize Unc-51-like kinase 1 protein, inhibit light chain 3 protein lipidation, and subsequently hinder autophagic flux, leading to increased α-globin deposition. Additionally, these mutations were associated with erythrotoxic effects in vitro, including increased intracellular reactive oxygen species levels, higher apoptosis rates, and impaired erythroid differentiation and maturation. This study sheds light on the molecular association between mutations in ATGs and the exacerbation of β-thalassemia, highlighting the potential role of the AMBRA1 gene as a promising diagnostic and therapeutic target for β-hemoglobinopathies.

Cervical cancer is the most common gynecologic cancer. Autophagy is involved in the progression of CCa. ULK1 is a crucial kinase in autophagy initiation. However, few studies have investigated the role of ULK1 phosphorylation at tyrosine residues in the progression of CCa, and the underlying mechanism remains elusive. In this study, we demonstrated that JAK2 is a novel upstream kinase that phosphorylates ULK1 at the tyrosine site. JAK2 interacts with and phosphorylates ULK1 at Tyr1007. The phosphorylation of ULK1 at Y1007 increases its activity and stability, activates autophagy, and promotes the progression of CCa. We further showed that the phosphorylation of ULK1 at Y1007 is a predictive marker of CCa patient outcome. Furthermore, we identified SRPK1 as a potential downstream substrate of ULK1 to promote the progression of CCa. Our research sheds light on the molecular mechanism of CCa progression, through JAK2/ULK1 axis, and emphasizes the phosphorylation of ULK1 at Y1007 as a predictor of CCa.

Repair of infectious bone defects remains a serious problem in clinical practice owing to the high risk of infection and excessive reactive oxygen species (ROS) during the early stage, and the residual bacteria and delayed Osseo integrated interface in the later stage, which jointly creates a complex and dynamic microenvironment and leads to bone non-union. The melatonin carbon dots (MCDs) possess antibacterial and osteogenesis abilities, greatly simplifying the composition of a multifunctional material. Therefore, a multifunctional hydrogel containing MCDs (GH-MCD) is developed to meet the multi-stage and complex repair needs of infectious bone injury in this study. The GH-MCD can intelligently release MCDs responding to the acidic microenvironment to scavenge intracellular ROS and exhibit good antibacterial activity by inducing the production of ROS in bacteria and inhibiting the expression of secA2. Moreover, it has high osteogenesis and long-lasting antimicrobial activity during bone repair. RNA-seq results reveal that the hydrogels promote the repair of infected bone healing by enhancing cellular resistance to bacteria, balancing osteogenesis and osteoclastogenesis, and regulating the immune microenvironment. In conclusion, the GH-MCD can promote the repair of infectious bone defects through the programmed transformation of the microenvironment, providing a novel strategy for infectious bone defects.

Individuals with genetic elimination of MLKL (mixed lineage kinase domain like pseudokinase) exhibit an increased susceptibility to neurodegenerative diseases like Alzheimer disease (AD). However, the mechanism is not yet fully understood. Here, we observed significant compromise in macroautophagy/autophagy in the brains of mlkl knockout (KO) mice, as evidenced by the downregulation of BECN1/Beclin1 and ULK1 (unc-51 like autophagy activating kinase 1). We identified UBA52 (ubiquitin A-52 residue ribosomal protein fusion product 1) as the binding partner of MLKL under physiological conditions. Loss of Mlkl induced a decrease in ubiquitin levels by preventing UBA52 cleavage. Furthermore, we demonstrated that the deubiquitinase (DUB) USP7 (ubiquitin specific peptidase 7) mediates the processing of UBA52, which is regulated by MLKL. Moreover, our results indicated that the reduction of BECN1 and ULK1 upon Mlkl loss is attributed to a decrease in their lysine 63 (K63)-linked polyubiquitination. Additionally, single-nucleus RNA sequencing revealed that the loss of Mlkl resulted in the disruption of multiple neurodegenerative disease-related pathways, including those associated with AD. These results were consistent with the observation of cognitive impairment in mlkl KO mice and exacerbation of AD pathologies in an AD mouse model with mlkl deletion. Taken together, our findings demonstrate that MLKL-USP7-UBA52 signaling is required for autophagy in brain through maintaining ubiquitin homeostasis, and highlight the contribution of Mlkl loss-induced ubiquitin deficits to the development of neurodegeneration. Thus, the maintenance of adequate levels of ubiquitin may provide a novel perspective to protect individuals from multiple neurodegenerative diseases through regulating autophagy.Abbreviations: 4HB: four-helix bundle; AAV: adeno-associated virus; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; APOE: apolipoprotein E; APP: amyloid beta precursor protein; Aβ: amyloid β; BECN1: beclin 1; co-IP: co-immunoprecipitation; DEGs: differentially expressed genes; DLG4: discs large MAGUK scaffold protein 4; DUB: deubiquitinase; EBSS: Earle's balanced salt solution; GFAP: glial fibrillary acidic protein; HRP: horseradish peroxidase; IL1B: interleukin 1 beta; IL6: interleukin 6; IPed: immunoprecipitated; KEGG: Kyoto Encyclopedia of Genes and Genomes; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MLKL: mixed lineage kinase domain like pseudokinase; NSA: necrosulfonamide; OPCs: oligodendrocyte precursor cells; PFA: paraformaldehyde; PsKD: pseudo-kinase domain; SYP: synaptophysin; UB: ubiquitin; UBA52: ubiquitin A-52 residue ribosomal protein fusion product 1; UCHL3: ubiquitin C-terminal hydrolase L3; ULK1: unc-51 like autophagy activating kinase 1; UMAP: uniform manifold approximation and projection; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; USP9X: ubiquitin specific peptidase 9 X-linked.

Under salt stress, autophagy regulates ionic balance, scavenges ROS, and supports nutrient remobilization, thereby alleviating osmotic and oxidative damage. Salt stress is a major environmental challenge that significantly impacts plant growth and agricultural productivity by disrupting nutrient balance, inducing osmotic stress, and causing the accumulation of toxic ions like Na+. Autophagy, a key cellular degradation and recycling pathway, plays a critical role in enhancing plant salt tolerance by maintaining cellular homeostasis and mitigating stress-induced damage. While autophagy has traditionally been viewed as a response to nutrient starvation, recent research has highlighted its importance under various environmental stresses, particularly salt stress. Under such conditions, plants activate autophagy through distinct signaling pathways involving autophagy-related genes (ATGs), Target of Rapamycin (TOR) proteins, and reactive oxygen species (ROS). Salt stress induces the expression of ATG genes and promotes the formation of autophagosomes, which facilitate the degradation of damaged organelles, denatured proteins, and the sequestration of Na+ into vacuoles, thereby improving stress tolerance. Recent studies have also suggested that autophagy may play a direct role in salt stress signaling, linking it to the regulation of metabolic processes. This review discusses the molecular mechanisms underlying autophagy induction in plants under salt stress, including the roles of ATGs and TOR, as well as the physiological significance of autophagy in mitigating oxidative damage, maintaining ion balance, and enhancing overall salt tolerance. In addition, we discussed the metabolic changes related to autophagy in stressed plants and examined the broader implications for managing plant stress and improving crops.

The nucleus is a highly specialized organelle that houses the cell's genetic material and regulates key cellular activities, including growth, metabolism, protein synthesis, and cell division. Its structure and function are tightly regulated by multiple mechanisms to ensure cellular integrity and genomic stability. Increasing evidence suggests that nucleophagy, a selective form of autophagy that targets nuclear components, plays a critical role in preserving nuclear integrity by clearing dysfunctional nuclear materials such as nuclear proteins (lamins, SIRT1, and histones), DNA-protein crosslinks, micronuclei, and chromatin fragments. Impaired nucleophagy has been implicated in aging and various pathological conditions, including cancer, neurodegeneration, autoimmune disorders, and neurological injury. In this review, we focus on nucleophagy in mammalian cells, discussing its mechanisms, regulation, and cargo selection, as well as evaluating its therapeutic potential in promoting human health and mitigating disease.Abbreviations: 5-FU: 5-fluorouracil; AMPK, AMP-activated protein kinase; ATG, autophagy related; CMA, chaperone-mediated autophagy; DRPLA: dentatorubral-pallidoluysian atrophy; ER, endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; HOPS, homotypic fusion and vacuole protein sorting; LIR: LC3-interacting region; MEFs: mouse embryonic fibroblasts; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; PCa: prostate cancer; PE: phosphatidylethanolamine; PI3K, phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; rRNA: ribosomal RNA; SCI: spinal cord injury; SCLC: small cell lung cancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SupraT: supraphysiological levels of testosterone; TOP1cc: TOP1 cleavage complexes.

Both CO2 retention, or hypercapnia, and skeletal muscle dysfunction predict higher mortality in critically ill patients. Mechanistically, muscle injury and reduced myogenesis contribute to critical illness myopathy, and while hypercapnia causes muscle wasting, no research has been conducted on hypercapnia-driven dysfunctional myogenesis in vivo. Autophagy flux regulates myogenesis by supporting skeletal muscle stem cell - satellite cell - activation, and previous data suggest that hypercapnia inhibits autophagy. We tested whether hypercapnia worsens satellite cell autophagy flux and myogenic potential and if autophagy induction reverses these deficits. Satellite cell transplantation and lineage-tracing experiments showed that hypercapnia undermined satellite cells' activation, replication, and myogenic capacity. Bulk and single-cell sequencing analyses indicated that hypercapnia disrupts autophagy, senescence, and other satellite cell programs. Autophagy activation was reduced in hypercapnic cultured myoblasts, and autophagy genetic knockdown phenocopied these changes in vitro. Rapamycin stimulation led to AMPK activation and downregulation of the mTOR pathway, which are both associated with accelerated autophagy flux and cell replication. Moreover, hypercapnic mice receiving rapamycin showed improved satellite cell autophagy flux, activation, replication rate, and posttransplantation myogenic capacity. In conclusion, we have shown that hypercapnia interferes with satellite cell activation, autophagy flux, and myogenesis, and systemic rapamycin administration improves these outcomes.

Autophagy is the process of reusing the body's senescent and damaged cell components, which can be regarded as the cellular circulatory system. There are 3 distinct forms of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. In the heart, autophagy is regulated mainly through mitophagy because of the metabolic changes of cardiomyocytes caused by ischemia and hypoxia. Myocardial remodeling is characterized by gradual heart enlargement, cardiac dysfunction, and extraordinary molecular changes. Cardiac remodeling after myocardial infarction is almost inevitable, which is the leading cause of heart failure. Autophagy has a protective effect on myocardial remodeling improvement. Autophagy can minimize cardiac remodeling by preventing misfolded protein accumulation and oxidative stress. This review summarizes the nestest molecular mechanisms of autophagy and myocardial remodeling, the protective effects, and the new target of autophagy medicine in cardiac remodeling. The future development and challenges of autophagy in heart disease are also summarized.

Diffuse large B-cell lymphoma (DLBCL) is the leading cause of mortality from invasive hematological malignancies worldwide. MicroRNA-7-5p (miR-7-5p) has been shown to be a tumor suppressor in several types of tumors. However, its role in DLBCL is not fully understood. This study explored the role of miR-7-5p in the progression of DLBCL and pursued the underlying mechanism. Quantitative real-time PCR and transfection of miRNA mimic and inhibitors were used to assess the effects of miR-7-5p on autophagy and apoptosis in SU-DHL-4 and SU-DHL-10 cells. Dual-luciferase reporter assay was used to identify target genes of miR-7-5p. Immunofluorescence, flow cytometry, and western blotting (WB) were performed to explore the underlying mechanism and downstream pathways of miR-7-5p and AMBRA1 in DLBCL cells. MiR-7-5p was upregulated in DLBCL cells. Luciferase reporter assays implicated AMBRA1 as a downstream target of miR-7-5p in DLBCL. WB and flow cytometry showed that an increase in miR-7-5p level and a decrease in AMBRA1 expression led to a decrease in autophagy and apoptosis-related protein expression. Furthermore, miR-7-5p prevented c-MYC dephosphorylation through AMBRA1 downregulation. On the contrary, c-MYC increased the expression of miR-7-5p, thereby establishing positive feedback on miR-7-5p transcription. The addition of hydroxychloroquine, an autophagy inhibitor, reduced autophagy and increased apoptosis in DLBCL cells. In vivo experiments further proved that the increase of miR-7-5p played a regulatory role in the expression of downstream AMBRA1 and c-MYC. These results demonstrate that c-MYC-dependent MiR-7-5p suppressed autophagy and apoptosis by targeting AMBRA1 in DLBCL cells. MiR-7-5p also suppressed autophagy and apoptosis by targeting AMBRA1 in DLBCL cells. Therefore, these data suggest that targeting miR-7-5p may be a promising strategy in DLBCL therapy.

The role of autophagy in host induced by infection of parasites of the Leishmania genus remains inadequately understood. Leishmania parasites modulate host macrophages to promote its survival by inducing autophagy response in the host cell. In this study, we conducted an investigation of L. major infection, focusing on host autophagy processes where we reconstructed two mathematical models elucidating autophagy induction and inhibition processes and its impact on parasite survival. Our models presented systems modulatory dynamics of the parasite-mediated host autophagy. Our work highlighted the pivotal role of signaling molecules associated with the immune response which included signaling induced by Toll-like receptor (TLR), specifically through regulation of JNK and AKT. Both molecules emerged as key regulators of host autophagy process, highlighting that JNK/AKT signaling axis may be a potential avenue for innovative therapeutic approaches in targeting leishmaniasis. Also, ATG16L complex was identified as a critical determinant in shaping the course of leishmanial infection through formation of autophagosomes. Through in vitro analyses in differentiated human monocyte cell line, we observed an increase in nitric oxide synthase (iNOS) concentration upon autophagy inhibition, while autophagy induction resulted in decreased iNOS concentration. This suggested that autophagy induction favors parasite survival in the host, potentially by providing a nutrient source that may be advantageous for the parasite. Inhibition of host autophagy promoted parasite elimination. Hence, our work proposed an avenue for strategically blocking host autophagy which enumerates a targeted approach for combating leishmaniasis.

The scaffold protein AMBRA1, which participates in the autophagy pathway, also promotes CD4+ T cell differentiation to Tregs independent of autophagy through its interactor PP2A. Here we have investigated the role of AMBRA1 in CD8+ T cell differentiation to cytotoxic T cells (CTL). AMBRA1 depletion in CD8+ T cells was associated with impaired expression of the transcription factors RUNX3 and T-BET that drive CTL differentiation and resulted in impaired acquisition of cytotoxic potential. These effects were recapitulated by pharmacological inhibition of the AMBRA1 activator ULK1 or its interactor PP2A. Based on the ability of PP2A to activate TFEB, we hypothesized a role for TFEB in the CTL differentiation program regulated by AMBRA1. We show that TFEB modulates RUNX3 and T-BET expression and the generation of killing-competent CTLs, and that AMBRA1 depletion, or ULK1 or PP2A inhibition, suppresses TFEB activity. These data highlight a role for AMBRA1, ULK1 and PP2A in CTL generation, mediated by TFEB, which we identify as a new pioneering transcription factor in the CTL differentiation program.

Autophagy-dependent survival relies on a crucial oscillatory response during cellular stress. Although oscillatory behaviour is typically associated with processes like the cell cycle or circadian rhythm, emerging experimental and theoretical evidence suggests that such periodic dynamics may explain conflicting experimental results in autophagy research. In this study, we demonstrate that oscillatory behaviour in the regulation of the non-selective, stress-induced macroautophagy arises from a series of interlinked negative and positive feedback loops within the mTORC1-AMPK-ULK1 regulatory triangle. While many of these interactions have been known for decades, recent discoveries have revealed how mTORC1, AMPK, and ULK1 are truly interconnected. Although these new findings initially appeared contradictory to established models, additional experiments and our systems biology analysis clarify the updated regulatory structure. Through computational modelling of the autophagy oscillatory response, we show how this regulatory network governs autophagy induction. Our results not only reconcile previous conflicting experimental observations but also offer insights for refining autophagy regulation and advancing understanding of its mechanisms of action.

Aging is a gradual and irreversible physiological process that significantly increases the risks of developing a variety of pathologies, including neurodegenerative, cardiovascular, metabolic, musculoskeletal, and immune system diseases. Mitochondria are the energy-producing organelles, and their proper functioning is crucial for overall cellular health. Over time, mitochondrial function declines causing an increased release of harmful reactive oxygen species (ROS) and DNA, which leads to oxidative stress, inflammation and cellular damage, common features associated with various age-related pathologies. The impairment of mitophagy, the selective removal of damaged or dysfunctional mitochondria by autophagy, is relevant to the development and progression of age-related diseases. The molecular mechanisms that regulates mitophagy levels in aging remain largely uncharacterized. AMBRA1 is an intrinsically disordered scaffold protein with a unique property of regulating the activity of both proliferation and autophagy core machineries. While the role of AMBRA1 during embryonic development and neoplastic transformation has been extensively investigated, its functions in post-mitotic cells of adult tissues have been limited due to the embryonic lethality caused by AMBRA1 deficiency. Recently, a key role of AMBRA1 in selectively regulating mitophagy in post-mitotic cells has emerged. Here we summarize and discuss these results with the aim of providing a comprehensive view of the mitochondrial roles of AMBRA1, and how defective activity of AMBRA1 has been functionally linked to mitophagy alterations observed in age-related degenerative disorders, including muscular dystrophy/sarcopenia, Parkinson diseases, Alzheimer diseases and age-related macular degeneration.Abbreviations: AD: Alzheimer disease; AMD: age-related macular degeneration; AMBRA1: autophagy and beclin 1 regulator 1; APOE4: apolipoprotein E4; ATAD3A: ATPase family AAA domain containing 3A; ATG: autophagy related; BCL2: BCL2 apoptosis regulator; BH3: BCL2-homology-3; BNIP3L/NIX: BCL2 interacting protein 3 like; CDK: cyclin dependent kinase; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CRL2: CUL2-RING ubiquitin ligase; DDB1: damage specific DNA binding protein 1; ER: endoplasmic reticulum; FOXO: forkhead box O; FUNDC1: FUN14 domain containing 1; GBA/β-glucocerebrosidase: glucosylceramidase beta; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IDR: intrinsically disordered region; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; MCL1: MCL1 apoptosis regulator, BCL2 family member; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MSA: multiple system atrophy; MYC: MYC proto-oncogene, bHLH transcription factor; NUMA1: nuclear mitotic apparatus protein 1; OMM; mitochondria outer membrane; PD: Parkinson disease; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PTK2/FAK: protein tyrosine kinase 2; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SAD: sporadic AD; SOCS3: suppressor of cytokine signaling 3; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; STAT3: signal transducer and activator of transcription 3; STING1: stimulator of interferon response cGAMP interactor 1; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; TGFB/TGFβ: transforming growth factor beta; TOMM: translocase of outer mitochondrial membrane; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; ULK1: unc-51 like autophagy activating kinase 1.

Autophagy is a conserved cellular process crucial for recycling cytoplasmic components and maintaining cellular homeostasis in eukaryotes. During autophagy, the formation of a protein complex involving AUTOPHAGY-RELATED PROTEIN 6 (ATG6) and phosphatidylinositol 3-kinase is pivotal for recruiting proteins involved in phagophore expansion. However, the intricate molecular mechanism regulating this protein complex in plants remains elusive.

Here, we aimed to unravel the molecular regulation of autophagy dynamics in Arabidopsis thaliana by investigating the involvement of the scaffold proteins 14-3-3λ and 14-3-3κ in regulating the proteolysis of ATG6. Phenotypic analyses revealed that 14-3-3λ and 14-3-3κ overexpression lines exhibited increased sensitivity to nutrient starvation, premature leaf senescence, and a decrease in starvation-induced autophagic vesicles, resembling the phenotypes of autophagy-defective mutants, suggesting the potential roles of 14-3-3 proteins in regulating autophagy in plants. Furthermore, our investigation unveiled the involvement of 14-3-3λ and 14-3-3κ in the RING finger E3 ligase SINAT1-mediated ubiquitination and destabilization of ATG6 in vivo. We also observed repressed turnover of ATG6 and translocation of GFP-ATG6 to mCherry-ATG8a-labelled punctate structures in the autophagy-defective mutant, which suggesting that ATG6 is probably a target of autophagy. Additionally, 14-3-3λ and 14-3-3κ interacted with Tumor necrosis factor Receptor Associated Factor 1a (TRAF1a) to promote the stability of TRAF1a in vivo under nutrient-rich conditions, suggesting a feedback regulation of autophagy. These findings demonstrate that 14-3-3λ and 14-3-3κ serve as scaffold proteins to regulate autophagy by facilitating the SINAT1-mediated proteolysis of ATG6, involving both direct and indirect mechanisms, in plants.

14-3-3 proteins regulate autophagy by directly or indirectly binding to ATG6 and SINAT1 to promote ubiquitination and degradation of ATG6. 14-3-3 proteins are involved in modulating autophagy dynamics by facilitating SINAT1-mediated ubiquitination and degradation of ATG6.

Osteoporosis (OP) is a widespread age-related disorder marked by decreased bone density and increased fracture risk, presenting a significant public health challenge. Central to the development and progression of OP is the dysregulation of the mechanistic target of the rapamycin (mTOR)-signaling pathway, which plays a critical role in cellular processes including autophagy, growth, and proliferation. The mTOR-autophagy axis is emerging as a promising therapeutic target due to its regulatory capacity in bone metabolism and homeostasis. This review aims to (1) elucidate the role of mTOR signaling in bone metabolism and its dysregulation in OP, (2) explore the interplay between mTOR and autophagy in the context of bone cell activity, and (3) assess the therapeutic potential of targeting the mTOR pathway with modulators as innovative strategies for OP treatment. By examining the interactions among autophagy, mTOR, and OP, including insights from various types of OP and the impact on different bone cells, this review underscores the complexity of mTOR's role in bone health. Despite advances, significant gaps remain in understanding the detailed mechanisms of mTOR's effects on autophagy and bone cell function, highlighting the need for comprehensive clinical trials to establish the efficacy and safety of mTOR inhibitors in OP management. Future research directions include clarifying mTOR's molecular interactions with bone metabolism and investigating the combined benefits of mTOR modulation with other therapeutic approaches. Addressing these challenges is crucial for developing more effective treatments and improving outcomes for individuals with OP, thereby unveiling the therapeutic potentials of targeting the mTOR-autophagy axis in this prevalent disease.

The Rab40 subfamily are unique small monomeric GTPases that form CRL5-based ubiquitin E3 ligase complex and regulate ubiquitylation of specific target proteins. Recent studies have shown that Rab40s play an important role in regulating cell migration, but the underlying mechanisms of Rab40/CRL5 complex function are still not fully understood. In this study we identified AMBRA1 as a novel binding partner of Rab40 GTPases and showed that this interaction mediates a bi-directional crosstalk between CRL4 and CRL5 E3 ligases. Importantly, we found that Rab40/CRL5 ubiquitylates AMBRA1, which does not result in AMBRA1 degradation, but instead it seems to induce AMBRA1-dependent regulation of gene transcription. The global transcriptional profiles identified by RNA-seq showed that AMBRA1 regulates transcription of genes related to cell adhesion and migration. Additionally, we have shown that AMBRA1-dependent transcription regulation does not require the enzymatic activity of AMBRA1/CRL4, and that Rab40-induced AMBRA1 ubiquitylation leads to dissociation of AMBRA1/CRL4 complex. Taken together, our findings reveal a novel function of Rab40/CRL5 complex as an important regulator for AMBRA1-dependent transcription of genes involved in cell migration.

Mitophagy significantly influences renal ischemia/reperfusion (I/R) injury and recovery. NLRX1 is recognized for its regulatory role in governing mitochondrial damage, autophagy, and the expression of pro-inflammatory factors. Despite the acknowledged involvement of NLRX1 in these crucial cellular processes, its specific function in renal I/R injury remains unclear. We detected the expression of NLRX1, the cGAS-STING pathway, and autophagy-related proteins using Western Blot analysis. RT-qPCR was utilized to measure the expression of NLRX1 mRNA and cytokines, and changes in mitochondrial DNA (mtDNA) within the cytoplasm. Immunofluorescence was applied to observe alterations in DNA distribution within the cytoplasm. The EtBr drug, which depletes mtDNA, and the Mdivi-1 mitophagy inhibitor, were used to verify the promotion of mitophagy by NLRX1. The results demonstrated that NLRX1 was downregulated after hypoxic/reoxygenation (H/R) injury, and there was an increase in cytoplasmic DNA. NLRX1 overexpression not only reduced IL-1β and IL-6 levels, but also decreased mtDNA in the cytoplasm. Additionally, NLRX1 further increases mitochondrial LC3 lipidation after H/R injury, and this effect is inhibited by Mdivi-1 drugs. The activation of the cGAS-STING pathway after H/R injury is inhibited by EtBr drugs and NLRX1. Co-immunoprecipitation results showed that NLRX1 could bind to STING. Moreover, inhibiting STING reversed NLRX1-induced mitochondrial LC3 lipidation. Our study reveals that NLRX1 can bind to STING to promote mitophagy and inhibits inflammation caused by mtDNA/cGAS/STING signaling.

Autophagy is an important lysosomal degradation process that digests and recycles bio-molecules, protein or lipid aggregates, organelles, and invaded pathogens. Autophagy plays crucial roles in regulation of metabolic and oxidative stress and multiple pathological processes. In cancer, the role of autophagy is dual and paradoxical. Ubiquitination has been identified as a key regulator of autophagy that can influence various steps in the autophagic process, with autophagy-related proteins being targeted for ubiquitination, thus impacting cancer progression and the effectiveness of therapeutic interventions. This review will concentrate on mechanisms underlying autophagy, ubiquitination, and their interactions in cancer, as well as explore the use of drugs that target the ubiquitin-proteasome system (UPS) and ubiquitination process in autophagy as part of cancer therapy.

Ischemia reperfusion (I/R) was considered as one of main causes of acute kidney injury (AKI). However, the exact mechanism remains unclear. Here, this study aimed to investigate the role and mechanism of the m6A demethylase fat mass and obesity-associated (FTO) protein in I/R-induced AKI. HK-2 cells and SD rats were utilized to establish hypoxia/reoxygenation (H/R) or I/R induced AKI models. The changes of RNAs and proteins were quantified using RT-qPCR, western blot, and immunofluorescence assays, respectively. Cell proliferation and apoptosis were assessed by CCK-8 and flow cytometry. Interactions between molecules were investigated using RIP, ChIP, Co-IP, RNA pull-down, and dual luciferase reporter assays. Global m6A quantification was evaluated by kits. TUNEL and HE staining were employed for histopathological examinations. Oxidative stress-related indicators and renal function were determined using ELISA assays. The FTO expression was downregulated in H/R-induced HK-2 cells and renal tissues from I/R-induced rats. Overexpression of FTO improved the cell viability but repressed apoptosis and oxidative stress in H/R-treated HK-2 cells, as well as enhanced renal function and alleviated kidney injury in I/R rats. Notably, the FTO overexpression significantly increased autophagy-related LC3 and ULK1 levels. When autophagy was inhibited, the protective effects of FTO in AKI were diminished. Notably, Ambra1, a crucial regulator of autophagy, was repressed in H/R-induced HK-2 cells. However, the FTO overexpression restored the Ambra1 expression by reducing m6A modification of its mRNA. SP1, acting as an upstream transcription factor, directly interacts with the FTO promoter to enhance FTO expression. Knockdown of SP1 or Ambra1 suppressed the beneficial effects of FTO upregulation on autophagy and oxidative stress injury in H/R-stimulated cells. FTO, transcriptionally activated by SP1, promoted autophagy by upregulating Ambra1/ULK1 signaling, thereby inhibiting oxidative stress and kidney injury. These findings may provide some novel insights for AKI treatment.

Autophagy is a fundamental pillar of cellular resilience, indispensable for maintaining cellular health and vitality. It coordinates the meticulous breakdown of cytoplasmic macromolecules as a guardian of cell metabolism, genomic integrity, and survival. In the complex play of biological warfare, autophagy emerges as a firm defender, bravely confronting various pathogenic, infectious, and cancerous adversaries. Nevertheless, its role transcends mere defense, wielding both protective and harmful effects in the complex landscape of disease pathogenesis. From the onslaught of infectious outbreaks to the devious progression of chronic lifestyle disorders, autophagy emerges as a central protagonist, convolutedly shaping the trajectory of cellular health and disease progression. In this article, we embark on a journey into the complicated web of molecular and immunological mechanisms that govern autophagy's profound influence over disease. Our focus sharpens on dissecting the impact of various autophagy-associated proteins on the kaleidoscope of immune responses, spanning the spectrum from infectious outbreaks to chronic lifestyle ailments. Through this voyage of discovery, we unveil the vast potential of autophagy as a therapeutic linchpin, offering tantalizing prospects for targeted interventions and innovative treatment modalities that promise to transform the landscape of disease management.

Autophagy is essential for cell survival and cellular homeostasis under various stress conditions. Therefore, autophagy dysfunction is associated with the pathogenesis of various human diseases. We explored the regulatory role of RhoBTB3 in autophagy and its interaction with activating molecules in AMBRA1. RhoBTB3 deficiency was found to induce autophagy, while its overexpression inhibited autophagy induction. Through immunoprecipitation and mass spectrometry, AMBRA1 was identified as a substrate of RhoBTB3. The study revealed that RhoBTB3 regulates AMBRA1 stability by influencing its protein levels without affecting its mRNA levels. RhoBTB3 induced the ubiquitination of AMBRA1, leading to proteasome-mediated degradation, with the ubiquitination occurring at K45 on AMBRA1 through a K27-linked ubiquitin chain. The knockdown of AMBRA1 blocked RhoBTB3 knockdown-induced autophagy, indicating the dependency of autophagy on AMBRA1. Thus, RhoBTB3 negatively regulates autophagy by mediating AMBRA1 ubiquitination and degradation, suggesting RhoBTB3 as a potential therapeutic target for autophagy-related diseases.

Autophagy initiation is regulated by the ULK1 kinase complex. To gain insights into functions of the holo-complex, we generated a deep interactome by combining affinity purification- and proximity labeling-mass spectrometry of all four complex members: ULK1, ATG13, ATG101, and RB1CC1/FIP200. Under starvation conditions, the ULK1 complex interacts with several protein and lipid kinases and phosphatases, implying the formation of a signalosome. Interestingly, several selective autophagy receptors also interact with ULK1, indicating the activation of selective autophagy pathways by nutrient starvation. One effector of the ULK1 complex is the HSC/HSP70 co-chaperone BAG2, which regulates the subcellular localization of the VPS34 lipid kinase complex member AMBRA1. Depending on the nutritional status, BAG2 has opposing roles. In growth conditions, the unphosphorylated form of BAG2 sequesters AMBRA1, attenuating autophagy induction. In starvation conditions, ULK1 phosphorylates BAG2 on Ser31, which supports the recruitment of AMBRA1 to the ER membrane, positively affecting autophagy.

Tudor Domain Containing 3 (TDRD3) is a methylarginine-reader protein that functions as a scaffold in the nucleus facilitating transcription, however TDRD3 is also recruited to stress granules (SGs) during the Integrated Stress Response (ISR) although its function therein remains largely unknown. We previously showed that TDRD3 is a novel antiviral restriction factor that is cleaved by virus 2A protease, and plays complex modulatory roles in both interferon and inflammatory signaling during stress and enterovirus infections. Here we have found that TDRD3 contains structural motifs similar to known selective autophagy receptors such as p62/SQSTM1, sharing ubiquitin associated domains (UBA) and LC3 interacting regions (LIR) that anchor cargo destined for autophagosomes to activated LC3 protein coating autophagosome membranes. This is of interest since enteroviruses hijack autophagy machinery to facilitate formation of viral replication factories, virus assembly and egress from the infected cell. Here we explored possible roles of TDRD3 in autophagy, hypothesizing that TDRD3 may function as a specialized selective autophagy receptor. We found that KO of TDRD3 in HeLa cells significantly reduces starvation induced autophagy, while its reintroduction restores it in a dose-dependent manner. Autophagy receptors are degraded during autophagy and expression levels decrease during this time. We found that TDRD3 levels decrease to the same extent as the autophagy receptor p62/SQSTM1 during autophagy, indicating autophagy-targeted turnover in that role. Knockout of TDRD3 or G3BP1 did not make significant changes in overall cell localization of LC3B or p62/SQSTM1, but did result in greater concentration of Lamp2 phagosome marker for phagosomes and phagolysosomes. To test the potential roles of TDRD3 in autophagic processes, we created a series of deletion mutants of TDRD3 lacking either UBA domain or the various LIR motifs that are predicted to interact with LC3B. Microscopic examination of starved cells expressing these variants of TDRD3 showed ΔLIR-TDRD3 had defects in colocalization with LC3B or Lamp2. Further, super resolution microscopy revealed ring structures with TDRD3 interfacing with p62/SQSTM1. In examination of arsenite induced stress granules we found recruitment of TDRD3 variants disrupted normally tight SG condensation, altered the decay rate of SGs upon release from stress and the kinetics of SG formation. We found evidence that the LIR3 motif on TDRD3 is involved in TDRD3 interaction with LC3B in coIP experiments, colocalization studies, and that this motif plays a key role in TDRD3 recruitment to SGs and SG resolution. Overall, these data support a functional role of TDRD3 in selective autophagy in a mode similar to p62/SQSTM1, with specific roles in SG stability and turnover. Enterovirus cleavage of TDRD3 likely affects both antiviral and autophagic responses that the virus controls for replication.

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

The protein homeostasis, or proteostasis, is maintained through the coupling of two pivotal systems: the ubiquitin-proteasome and autophagy. Cumulative evidence has suggested E3 ubiquitin ligases specifically play a central role in this coupling, ensuring the regulation of synaptic and cognitive functions. Defects in these ligases have been identified as hallmarks in a range of neurodevelopmental and neurodegenerative disorders. Recent literature has spotlighted the E3 ubiquitin ligase, UBE3A, as a key player in this domain. Dysregulation or loss of UBE3A function has been linked to disrupted proteostasis, leading to synaptic and cognitive anomalies. Notably, such defects are prominently observed in conditions like Angelman syndrome, a neurodevelopmental disorder characterized by severe cognitive impairments. The emerging understanding of UBE3A's role in bridging the ubiquitin-proteasome and autophagy systems offers a promising therapeutic avenue. Targeting the defective pathways caused by UBE3A loss could pave the way for innovative treatments, potentially ameliorating the cognitive deficits observed in neurological disorders like Angelman syndrome. As the scientific community delves deeper into the molecular intricacies of E3 ubiquitin ligases, there is burgeoning hope for devising effective interventions for associated neurological conditions.