The tripartite motif (TRIM) family member TRIM15 is an E3 ubiquitin ligase that is abnormally expressed in a variety of tumors, but its role and mechanism in high-grade serous ovarian cancer (HGSOC) are unclear. Here, we found for the first time that TRIM15 was upregulated in HGSOC and was associated with poor overall survival. Functional experiments showed that TRIM15 drove the proliferation of HGSOC cells and inhibited the apoptosis of tumor cells in vivo and in vitro. In terms of mechanism, we found that TRIM15 contributed to the malignant proliferation of HGSOC cells by promoting the activation of AKT and that there was a direct binding between them. TRIM15 induced lysine-63 (K63) ubiquitination of AKT through its Ring domain, which in turn activated the AKT signaling pathway. In addition, TRIM15-mediated K63 ubiquitination occurs mainly in the pleckstrin homology (PH) domain of AKT. We further identified other proteins and their functions regulated by TRIM15 in HGSOC cells by ubiquitin proteomic analysis. Furthermore, hypoxia-inducible factor-1α promoted TRIM15 transcriptional activation by binding to the hypoxia response elements of the TRIM15 promoter. Our study suggests that TRIM15 induces K63 ubiquitination of the AKT PH domain through its Ring domain and activates the AKT signaling pathway, thereby promoting HGSOC progression. In addition, the abnormally high expression of TRIM15 was associated with the hypoxic microenvironment of HGSOC tissues.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses pathologies from simple steatosis and steatohepatitis (MASH) to cirrhosis. Hepatic inflammation is a common cause of liver pathogenesis, with macrophage activation as a key indicator of both acute and chronic liver dysfunction. While M1 macrophages promote inflammation and M2 macrophages suppress it, their roles in MASLD are dynamic and shift according to disease stage and liver microenvironment. Tripartite motif (TRIM) family proteins, which possess E3 ubiquitin ligase activity, are involved in various cellular processes, including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. TRIM38 negatively regulates innate immunity and inflammation triggered by viruses, Toll-like receptor 3 and 4, and tumor necrosis factor α/interleukin-1β signaling; however, its role in liver pathogenesis remains unclear. This study investigates the role of macrophage TRIM38 in metabolic liver disease to identify key targets for controlling inflammation. TRIM38 overexpression suppressed lipopolysaccharide-induced macrophage activation and metabolic stress-induced hepatic lipid accumulation. Mechanistically, TRIM38 interacted with heat shock protein family A member 5 (HSPA5) and stabilized it via K63-dependent ubiquitination. This TRIM38-HSPA5 axis promoted the expression of M2 macrophage markers (arginase 1 and retinoic acid-related orphan receptor α), thereby ameliorating liver steatosis. Single-cell RNA sequencing revealed significant downregulation of TRIM38 expression in the liver macrophages of patients with MASLD and negative regulation of liver inflammation via modulation of macrophage polarization. Hence, macrophage TRIM38 suppresses metabolic liver disease progression via HSPA5-mediated M2 macrophage polarization and provides insights into potential therapeutic targets.

Ovarian cancer represents a significant threat to women's health. and ferroptosis is recognized as a potential natural inhibitor in cancer therapy, the regulatory mechanism of TRIM25 in ovarian cancer and its potential for regulating ferroptosis as a treatment remain unclear.

The role of TRIM25 in ovarian cancer was examined through functional gain- and loss-of-function assays both in vitro and in vivo, while its target genes were identified. The stability and ubiquitination sites of PIEZO1 were analyzed using protein docking and ubiquitination experiments.

TRIM25 is highly expressed in ovarian cancer and promotes the growth and metastasis of ovarian cancer cells both in vivo and in vitro. Mechanistically, it facilitates PIEZO1 degradation through ubiquitination-dependent proteasome activity, inhibits ferroptosis, and stimulates ovarian cancer cell growth.

Our study clearly shows that TRIM25 stimulates ovarian cancer by inducing K63-linked ubiquitination of PIEZO1, which suppresses ferroptosis and promotes excessive proliferation of ovarian cancer cells. Further research identified the ubiquitination modification site on PIEZO1, providing insights for ovarian cancer treatment.

Gliomas, the most prevalent malignant primary brain tumors in adults, represent a heterogeneous group of neoplasms characterized by poor prognosis and limited therapeutic options, particularly in high-grade cases. Understanding the molecular mechanisms underlying glioma pathogenesis is crucial for developing novel and effective treatment strategies. In recent years, increasing attention has been directed toward the tripartite motif (TRIM) family of proteins, a class of E3 ubiquitin ligases, due to their significant roles in glioma development and progression. This review comprehensively explores the diverse functions of TRIM proteins in gliomas, including their expression patterns, prognostic significance, and mechanisms of action that are both ubiquitination-dependent and -independent. By synthesizing current knowledge, we aim to elucidate the role of TRIM proteins in glioma pathogenesis and identify potential therapeutic targets within this protein family.

Castrate-resistant prostate cancer (CRPC) is a likely outcome of hormone treatment for advanced prostate cancer. Although no longer dependent on androgen levels, CRPC remains driven by the androgen receptor (AR). One proposed progression mechanism is altered repertoires of coregulator proteins possessing the ability to alter AR activity. Increased expression of tripartite motif-containing 24 (TRIM24) and TRIM28-two members of a distinct bromodomain-containing subfamily of Tripartite motif (TRIM) coregulators-occurs in CRPC. Endogenous TRIM24 and TRIM28 interact with each other and AR, bind to chromatin and regulate genes such as the angiogenic factor vascular endothelial growth factor A (VEGFA) and oncogene MYC. Silencing of TRIM24 and TRIM28 simultaneously, but not either alone, sensitised CRPC model cell lines to the antiandrogen enzalutamide and bicalutamide. This re-sensitisation to antiandrogen therapeutics could then be reversed by addition of VEGF. Furthermore, both TRIM24 and TRIM28 expression associated with angiogenesis signatures in tumour samples, and conditioned media from TRIM24 and TRIM28-silenced cancer cells inhibited endothelial cell proliferation and formation of vascular tube structures. Our data suggest that TRIM24 and TRIM28 proteins interact, in gene-specific manners, to regulate AR activity, increase VEGF signalling and angiogenesis, and that targeting these coregulators may increase the effectiveness of antiandrogen therapy.

Tripartite motif (TRIM) family proteins are increasingly recognized as important regulators of autophagy under various physiological and pathological conditions. TRIM22 has been previously shown to mediate autophagosome-lysosome fusion, but its potential role in earlier stages of autophagy remained unexplored. In this study, we investigated the function of TRIM22 in autophagy initiation. Overexpression of TRIM22 increased LC3-II levels and enhanced autophagic flux without affecting mTOR and AMPK activity. We found that TRIM22 interacts with components of both the ULK1 complex and the class III PI3K complex through distinct domains, recruiting them into punctate structures that represent autophagosome formation sites. Domain mapping revealed that the SPRY domain mediates interactions with ATG13 and FIP200, while the N-terminal region interacts with ULK1 and ATG101. The B-box domain of TRIM22 was identified as crucial for its interaction with Beclin-1, a key component of the class III PI3K complex. Deletion of this domain impaired the ability of TRIM22 to assemble the class III PI3K complex and induce autophagic flux. Interestingly, competitive binding assays revealed that Beclin-1 and PLEKHM1 bind to the same region of TRIM22, suggesting a mechanism for coordinating different stages of autophagy. The Alzheimer's disease-associated TRIM22 variant R321K maintained autophagy initiation function in both cell lines and primary neurons. These findings demonstrate that TRIM22 acts as a scaffold protein to promote autophagy initiation, in addition to its previously described role in autophagosome-lysosome fusion. Our study provides new insights into the molecular mechanisms by which TRIM proteins regulate multiple stages of the autophagy process.

RPA2, a key component of the RPA complex, is essential for single-stranded DNA (ssDNA) binding and DNA repair. However, the regulation of RPA2-ssDNA interaction and the recruitment of repair proteins following DNA damage remain incompletely understood. Our study uncovers a novel mechanism by which phosphorylated TRIM21 (Phospho-TRIM21) regulates RPA2 ubiquitination, thereby modulating homologous recombination and tumor radio/chemo-resistance. In the absence of DNA damage, TRIM21 mediates K63-linked ubiquitination of RPA2, countering K6-linked ubiquitination. Upon DNA damage, ubiquitination-modified RPA2 binds ssDNA, stabilizing the DNA structure and facilitating ATRIP/ATR recruitment. ATR subsequently phosphorylates TRIM21 at Ser41, leading to the dissociation of the TRIM21-RPA2 complex and a shift in RPA2 ubiquitination from K63 to K6 linkage. This shift maintains RPA2 ubiquitination homeostasis and stabilizes the RPA2-ATRIP complex, which is crucial for efficient homologous recombination (HR) repair and enhanced tumor radio/chemo-resistance. We also demonstrate that TRIM21 is frequently upregulated in cancers, and its depletion sensitizes cancer cells to radio/chemotherapy, suggesting its potential as a therapeutic target. This study provides novel insights into TRIM21's role in the DNA damage response and its implications for cancer treatment.

The large yellow croaker (Larimichthys crocea) is a cornerstone species in Chinese marine aquaculture, yet bacterial infections-particularly visceral white nodules disease (VWND) caused by Pseudomonas plecoglossicida-severely compromise its production. This study aimed to elucidate the immunoregulatory mechanisms of tripartite motif-containing protein 38 in the large yellow croaker (Lctrim38) during bacterial infections, with an emphasis on host-pathogen interactions involving P. plecoglossicida, to evaluate its potential for disease-resistant breeding applications. The full-length cDNA of Lctrim38 was cloned and characterized, with structural analysis revealing a conserved domain architecture comprising RING, B-box, coiled-coil, and PRY-SPRY motifs. Functional characterization through Lctrim38 overexpression in large yellow croaker kidney cells (PCK cells) demonstrated significant modulation of key immune-related pathways, including TGF-β, PI3K-Akt, IL-17, and PPAR. Notably, Lctrim38-mediated inhibition of NF-κB signaling was shown to downregulate pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ), establishing its role as a negative regulator of inflammatory responses. These findings provide insights into the immune mechanisms of Trim38 in large yellow croakers and highlight its potential as a molecular target for disease resistance breeding. Future research should explore its broader functions, including its antiviral potential.

Rationale: Prostate cancer (PCa) growth is facilitated by the androgen receptor (AR) and its downstream signaling pathways, making AR-targeted therapy crucial for treating advanced stages. Despite this, the response to AR-targeted therapies is inconsistent, with a significant proportion of patients even exhibiting unresponsiveness to therapy from the outset, known as primary resistance. Therefore, a refined categorization framework is imperative for the timely detection of resistant phenotypes and the exploration of novel therapeutic avenues. Methods: Tissue microarrays and clinical cohorts were employed to delineate the impact of APOE on the prognostic outcomes and therapeutic resistance in PCa patients. Employing flow cytometry, immunoprecipitation, and mass spectrometry, we dissected the molecular underpinnings of APOE's role in conferring resistance to AR-targeted interventions. Single-cell RNA sequencing elucidated the intricate transcriptomic profiles of PCa with elevated APOE expression. Additionally, the therapeutic potential of anti-PD-L1 agents in treating PCa with APOE induction was rigorously assessed. Results: In this study, we elucidated the pivotal role of APOE in mediating primary resistance to AR-targeted therapy in PCa through the suppression of AR signaling pathways. Mechanistically, APOE was found to enhance the ubiquitination and subsequent degradation of AR by mediating the interaction between the E3-ligase TRIM25 and AR, concurrently dampening the transcriptional activity of AR. Additionally, elevated APOE expression was correlated with an augmented response to anti-PD-L1 treatment, hinting at the therapeutic advantage of immunotherapy in APOE-high PCa contexts. Conclusions: APOE expression could serve as a prognostic biomarker, pivotal for forecasting responses to both AR-targeted therapy and immunotherapy, thereby offering an innovative strategy for the personalized selection of treatment modalities in PCa.

Maintaining protein homeostasis is vital for multiple myeloma (MM) cell survival. Indirubin- 3-monoxime (I3MO), a potential MM therapeutic, inhibits proteasome activity, while histone deacetylase 6 (HDAC6) regulates autophagy. We developed I3MV- 8b, an I3MO derivative, integrating an HDAC6 inhibitor moiety to enhance dual inhibition of proteasome and autophagy pathways.

The anti-MM effects of I3MV- 8b were tested in vitro and in vivo. To identify downstream targets, RNA-seq and dual-luciferase reporter assays were performed. Additionally, ChIP-seq and IP-MS techniques were employed to elucidate the underlying molecular mechanism.

I3MV- 8b significantly suppressed MM cell proliferation and induced apoptosis. Combined with proteasome inhibitors, I3MV- 8b enhanced cytotoxicity by concurrently inhibiting proteasome and autophagy pathways. It reduced TRIM28 transcription, correlating with lower expression of proteasome subunits and autophagy-related genes. ChIP-seq revealed that TRIM28 binds to proteasome gene promoters, and its knockdown decreased proteasome subunit expression and activity. TRIM28 knockdown also impaired autophagosome formation. IP-MS and Co-IP assays showed TRIM28 interacted with 14-3 - 3ζ, a negative regulator of autophagy, promoting its ubiquitination and degradation. This interaction reduced autophagy regulation, further sensitizing cells to treatment.

I3MV- 8b offers a novel dual inhibition strategy targeting proteasome and autophagy, presenting a promising therapeutic option for MM.

Emerging evidence reveals the pivotal function of tripartite motif protein (TRIM) in colorectal cancer (CRC). However, the precise function of TRIM38 and its underlying mechanism in CRC remains to be elucidated, especially regarding its putative ubiquitination function. Here, it is identified that TRIM38 is downregulated in CRC tissues by DNA hypermethylation of its promoter. Further analysis demonstrates that decreased TRIM38 is correlated with unfavorable clinical features and poor prognosis. Moreover, TRIM38 functions as a tumor suppressor by inhibiting cell proliferation, metastasis, and AOM/DSS-induced tumorigenesis in CRC cells. Mechanistically, TRIM38 binds to the substrate protein CCT6A, leading to the degradation and K48-linked ubiquitination of CCT6A at the K127/K138 residues. The elevation of CCT6A protein level caused by TRIM38 downregulation diminishes the degradation of c-Myc protein, thereby activating the MYC pathway. The study elucidates a novel mechanism of TRIM38/CCT6A/c-Myc axis regulating CRC, potentially offering a new therapeutic target for its treatment.

In mammals, the activation of thermogenic adipocytes, such as beige and brown adipocytes, can significantly increase overall energy expenditure, offering a promising strategy to combat metabolic diseases. Despite its considerable potential, the regulatory mechanisms governing this activation remain largely elusive. This study bridges this gap by elucidating that tripartite motif 56 (TRIM56), an E3 ubiquitin ligase, is upregulated in response to cold stimuli, thereby promoting the recruitment of beige adipocytes. Notably, the overexpression of TRIM56 in adipocytes is shown to help mice maintain a core temperature under cold conditions, as well as confer protection against diet-induced obesity. Mechanistically, TRIM56 facilitates the degradation of the transducin-like enhancer protein 3 (TLE3) protein by promoting its K48-linked ubiquitination, which subsequently triggers the activation of thermogenic genes in subcutaneousl white adipose tissue and improved the metabolic profiles. These findings unveil a novel function for TRIM56 in adipocyte browning, suggesting its potential as a therapeutic target for the treatment of metabolic disorders.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver condition globally, lacks adequate and effective therapeutic remedies in clinical practice. Recent studies have increasingly highlighted the close connection between the ubiquitin-proteasome system (UPS) and the progression of MASLD. This relationship is crucial for understanding the disease's underlying mechanism. As a sophisticated process, the UPS govern protein stability and function, maintaining protein homeostasis, thus influencing a multitude of elements and biological events of eukaryotic cells. It comprises four enzyme families, namely, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin-protein ligases (E3), and deubiquitinating enzymes (DUBs). This review aims to delve into the array of pathways and therapeutic targets implicated in the ubiquitination within the pathogenesis of MASLD. Therefore, this review unveils the role of ubiquitination in MASLD while spotlighting potential therapeutic targets within the context of this disease.

Chromatin contains not only heterochromatin (HC) and euchromatins (EC) but also facultative heterochromatin (fHC), which experience the dynamic remodeling between HCs and ECs by different regulators. The regulation of fHCs involves lots of different cell functions, like genomic stability and gene transcription. Heterochromatin protein 1 (HP1) recognizes methylated H3K9 and reshapes the chromatin into the fHCs through liquid-liquid phase separation (LLPS). Among the three members of the HP1 family, HP1α can condensate by itself and HP1β forms granules with the help of TRIM28, while the HP1γ cannot phase separation alone either and the coordinator is still unclear. So, in this study, we investigated the molecular mechanism of how HP1γ interacts with TRIM66 through PxVxL motif. Based on that, we examined the key regions that controlled the TRIM66-HP1γ co-phase separation behaviors both in vitro and in vivo. Furthermore, we proved that the liquid granules of TRIM66-HP1γ and chromatin highly correlated with H3K9me3 sites, which indicated the relationship with DNA damage response. Finally, combined with our previous study, we proposed the system for how TRIM66 remodeled the chromatin into compressed fHC through the TRIM66-HP1γ-H3K9me3 axis with liquid-liquid phase separation.

Tripartite motif-containing proteins (TRIMs), comprising the greatest subfamily of E3 ubiquitin ligases with approximately 80 members of this family, are widely distributed in mammalian cells. TRIMs actively participate in ubiquitination of target proteins, a type of post-translational modification associated with protein degradation and other functions. Tripartite motif-containing protein 29 (TRIM29), a member of the TRIM family, differs from other members of this family in that it lacks the RING finger structural domain containing cysteine and histidine residues that mediates DNA binding, protein-protein interactions, and ubiquitin ligase, at its N-terminus. The expression of TRIM29 was initially found to be associated with cancer and diabetic nephropathy progression, and antiviral immunity which is triggered by virus-derived nucleic acids binding to pattern recognition receptors (PRRs) on immune cells. Recently, TRIM29 has also been explored as a diagnostic biomarker and therapeutic target for some immune-related diseases. Here, we review the functions of TRIM29 in the progression of diseases and the inherent mechanisms, as well as the remaining gaps in the literature. A thorough understanding of the detailed regulatory mechanisms of TRIM29 will ultimately facilitate the development of different therapeutic strategies for various diseases.

MAGEA4 is a member of the Melanoma-Associated Antigen (MAGE) family, characterized by high expression in various tumor tissues but low expression in normal tissues, with the exception of testis and placenta. Its expression is associated with poor prognosis in cancer. This review summarizes the mechanisms of action, regulatory functions, and immunotherapeutic applications of MAGEA4 in cancer.MAGEA4 promotes tumor initiation and progression through multiple pathways, including ubiquitination and degradation of the tumor suppressor P53, regulation of cell cycle and apoptosis, modulation of DNA damage repair, and enhancement of cancer cell survival. By forming a complex with TRIM28, MAGEA4 accelerates tumor development via P53 degradation. Factors such as TWIST1 and BORIS can upregulate MAGEA4 expression. MAGEA4 interacts with proteins including Miz-1, p53, and RAD18, participating in gene transcription regulation and DNA damage repair. By stabilizing RAD18, MAGEA4 facilitates the recruitment of Y-family DNA polymerases, enabling cells to continue replication under DNA damage conditions and thus supporting cancer cell survival. MAGEA4-based TCR-T cell therapy and cancer vaccines show clinical potential. This article comprehensively reviews the structure and function of MAGEA4, as well as recent research progress in solid tumors, providing a theoretical foundation for the clinical translation of MAGEA4 and its application in immunotherapy.

Gastric cancer (GC) stands as one of the most formidable malignancies worldwide. It is well-established that miRNAs play a crucial role in the initiation and progression of various human cancers. Among these, miR-99a-3p has been implicated in the pathogenesis of GC. In the context of our study, we embarked on the comprehensive examination of miR-99a-3p expression in GC cells. Additionally, we sought to establish a correlation between miR-99a-3p expression levels and the overall survival (OS) of GC patients, and our findings hinted at its potential role in predicting an unfavorable prognosis. To further investigate the functional implications of miR-99a-3p in GC, we conducted a series of cell-based experiments after successfully knocking down miR-99a-3p. These investigations uncovered a substantial inhibition of cellular events associated with tumor progression. Moreover, employing TargetScan, we identified Tripartite motif-containing protein 21 (TRIM21) as a putative target with a binding site for miR-99a-3p. Subsequent dual-luciferase reporter gene assay confirmed the direct interaction between miR-99a-3p and TRIM21. Western blot analysis validated the alteration in TRIM21 expression levels, revealing an upregulation upon miR-99a-3p knockdown. Building on these molecular findings, we extended our investigations to human GC tissues, where we observed a downregulation of TRIM21, which, notably, correlated with shorter overall survival. Lastly, to further solidify our conclusions, we conducted a series of in vitro and in vivo rescue experiments, collectively suggesting that miR-99a-3p promoted the progression of GC cells through the downregulation of TRIM21. In summary, our study comprehensively explored the role of miR-99a-3p in GC, revealing its association with unfavorable patient outcomes, functional implications in tumor progression, and a direct regulatory relationship with TRIM21. These findings collectively underscore the significance of miR-99a-3p in the pathogenesis of GC and present a potential therapeutic avenue for further investigation.

Tripartite motif-containing 47 (TRIM47) is a member of the TRIM family, which has E3 ligase activity and has been demonstrated to be involved in tumor development. In this work, we found that TRIM47 is highly expressed in head and neck squamous cell carcinomas (HNSCC) tissues. TRIM47 overexpression promoted HNSCC cell proliferation. Downregulation of TRIM47 suppressed HNSCC cell proliferation and promoted apoptosis and autophagy. TRIM47 suppression caused cell proliferation inhibition and apoptosis promotion could be reversed by 3-MA, an autophagy inhibitor. In mechanism, TRIM47 interacted with XIAP-associated factor 1 (XAF1), promoting its ubiquitination and degradation. XAF1 promoted HNSCC cell apoptosis and autophagy. TRIM47 overexpression caused cell proliferation promotion and autophagy inhibition could be reversed by XAF1 overexpression. Animal experiments confirmed that the knockdown of TRIM47 inhibits tumor growth in vivo. Ultimately, TRIM47 promotes the ubiquitination and degradation of XAF1 and suppresses apoptosis and autophagy to promote the progression of HNSCC.

Therapy resistance still constitutes a common hurdle in the treatment of many human cancers and is a major reason for treatment failure and patient relapse, concomitantly with a dismal prognosis. In addition to "intrinsic resistance", e.g., acquired by random mutations, cancer cells typically escape from certain treatments ("acquired resistance") by a large variety of means, including suppression of apoptosis and other cell death pathways via upregulation of anti-apoptotic factors or through inhibition of tumor-suppressive proteins. Therefore, ideally, the tumor-cell-restricted induction of apoptosis is still considered a promising avenue for the development of novel, tumor (re)sensitizing therapies. A growing body of evidence has highlighted the multifaceted role of tripartite motif 25 (TRIM25) in controlling different aspects of tumorigenesis, including chemotherapeutic drug resistance. Accordingly, overexpression of TRIM25 is observed in many tumors and frequently correlates with a poor patient survival. In addition to its originally described function in antiviral innate immune response, TRIM25 can play critical yet context-dependent roles in apoptotic- and non-apoptotic-regulated cell death pathways, including pyroposis, necroptosis, ferroptosis, and autophagy. The review summarizes current knowledge of molecular mechanisms by which TRIM25 can interfere with different cell death modalities and thereby affect the success of currently used chemotherapeutics. A better understanding of the complex repertoire of cell death modulatory effects by TRIM25 is an essential prerequisite for validating TRIM25 as a potential target for future anticancer therapy to surmount the high failure rate of currently used chemotherapies.

Lipids are crucial for various cellular functions. Besides the storage of energy equivalents, these include forming membrane bilayers and serving as signaling molecules. While significant progress has been made in the comprehension of the molecular and cellular biology of lipids, their functions in the cell nucleus remain poorly understood. The main role of the eukaryotic cell nucleus is to provide an environment for the storage and regulation of chromatin which is a complex of DNA, histones, and associated proteins. Recent studies suggest that nuclear lipids play a role in chromatin regulation and epigenetics. Here, we discuss various experimental methods in lipid-chromatin research, including biophysical, structural, and cell biology approaches, pointing out their strengths and weaknesses. We take the view that nuclear lipids have a far more widespread impact on chromatin than is currently acknowledged. This gap in comprehension is mostly due to existing experimental challenges in the study of lipid-chromatin biology. Several new, interdisciplinary approaches are discussed that could aid in elucidating the roles of nuclear lipids in chromatin regulation and gene expression.

This study utilized transcriptomic sequencing combined with cellular and animal models to explore the potential mechanisms of Xuebijing in treating sepsis-induced myocardial dysfunction, also known as sepsis-induced myocardial injury.

We investigated potential targets and regulatory mechanisms of XBJ injection using network pharmacology and RNA sequencing. The effects of XBJ on oxidative stress and apoptosis levels in human cardiac myocytes (AC16) and C57BL/6 mice exposed to lipopolysaccharide (LPS) were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA), fluorescent probe, Fluorescent Quantitative Polymerase Chain Reaction (qPCR), Western Blot, Transmission Electron Microscopy, oxidative stress-related indicators detection kit, flow cytometry, and Immunohistochemistry (IHC).

First, it was verified that XBJ can reduce the deformation of AC16 cardiomyocytes induced by LPS and the production and secretion of ROS (P <0.01). The transcriptome sequencing results showed that the TRIM16 gene was significantly increased after XBJ treatment, and the data of KEGG and GO analyses demonstrated that XBJ could inhibit the pathway expression of oxidative stress damage in AC16 cells, and PCR verified that XBJ could indeed increase the expression level of TRIM16 gene in AC16 cells (P <0.01). Basic animal and cell experiments showed that LPS could inhibit the expression of TRIM16 and NRF2 in cardiomyocytes (P <0.05) and promote the expression of Keap1 (P <0.01), while XBJ could significantly upregulate the expression levels of TRIM16 and NRF2 (P <0.01) and inhibit the expression of Keap1 (P <0.01), thereby affecting the expression levels of downstream proinflammatory cytokines and alleviating LPS-induced oxidative stress damage. In addition, XBJ also inhibited the expression of the pro-apoptotic proteins Bax and c-caspase3 (P <0.01), promoted the expression of the anti-apoptotic protein Bcl2 (P <0.01), and reduced LPS-induced apoptosis by upregulating TRIM16.

Our comprehensive data demonstrated that TRIM16 is a key gene in the therapeutic action of Xuebijing in sepsis-induced myocardial dysfunction, protecting myocardial cells from injury through antioxidative stress and anti-apoptotic mechanisms.

Cancer cells undergo metabolic adaptation to promote their survival and growth under energy stress conditions, yet the underlying mechanisms remain largely unclear. Here, we report that tripartite motif-containing protein 2 (TRIM2) is upregulated in response to glutamine deprivation by the transcription factor cyclic AMP-dependent transcription factor (ATF4). TRIM2 is shown to specifically interact with carnitine O-palmitoyltransferase 1 (CPT1A), a rate-limiting enzyme of fatty acid oxidation. Via this interaction, TRIM2 enhances the enzymatic activity of CPT1A, thereby regulating intracellular lipid levels and protecting cells from glutamine deprivation-induced apoptosis. Furthermore, TRIM2 is able to promote both in vitro cell proliferation and in vivo xenograft tumor growth via CPT1A. Together, these findings establish TRIM2 as an important regulator of the metabolic adaptation of cancer cells to glutamine deprivation and implicate TRIM2 as a potential therapeutic target for cancer.

Tripartite motif (TRIM) family proteins, distinguished by their N-terminal region that includes a Really Interesting New Gene (RING) domain with E3 ligase activity, two B-box domains, and a coiled-coil region, have been recognized as significant contributors in carcinogenesis, primarily via the ubiquitin-proteasome system (UPS) for degrading proteins. Mechanistically, these proteins modulate a variety of signaling pathways, including Wnt/β-catenin, PI3K/AKT, and TGF-β/Smad, contributing to cellular regulation, and also impact cellular activities through non-signaling mechanisms, including modulation of gene transcription, protein degradation, and stability via protein-protein interactions. Currently, growing evidence indicates that TRIM proteins emerge as potential regulators in gastric cancer, exhibiting both tumor-suppressive and oncogenic roles. Given their critical involvement in cellular processes and the notable challenges of gastric cancer, exploring the specific contributions of TRIM proteins to this disease is necessary. Consequently, this review elucidates the roles and mechanisms of TRIM proteins in gastric cancer, emphasizing their potential as therapeutic targets and prognostic factors.

While most Tripartite motif (TRIM) family proteins are E3 ubiquitin ligases, some members have functions beyond the regulation of ubiquitination, impacting normal physiological processes and disease progression. TRIM29, an important member of the TRIM family, exerts a predominant influence on cancer growth, epithelial-to-mesenchymal transition, stemness and metastatic progression by directly potentiating multiple canonical oncogenic pathways. The cancer-promoting effect of TRIM29 is also evident in metabolic interventions and interference with the efficacy of cancer therapeutics. As expected for any key node in cancer, the expression of TRIM29 is tightly regulated by non-coding RNAs, epigenetic modulation, and post-translational regulation. A systematic discussion of how TRIM29 is regulated in cancer, its influences on cancer progression, and its impact on cancer therapeutics is presented in this review. We also explore the context-dependent alterations between TRIM29 function from oncogenic to tumor suppression. As TRIM29 is involved in multiple aspects of cancer progression, a better understanding of its biological impact in cancer may help improve prognosis and develop novel therapeutic combinations, leading to improved personalized cancer care.

Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates. As E3 ubiquitin ligases, proteins of tripartite motif (TRIM) family play a role in cancer signaling, development, apoptosis, and formation. These proteins regulate diverse biological activities and signaling pathways. This study comprehensively outlines the functions of TRIM proteins in gastrointestinal physiology, contributing to our knowledge of the molecular pathways involved in gastrointestinal tumors. Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates.

The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells.

Dysregulation of redox homeostasis is associated with developing hepatocellular carcinoma (HCC). Oxidative stress (OS) is distinguished by the accumulation of ROS, which plays a variety of roles in cancer pathology. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, has anti-cancer pharmacological activity. However, the regulatory mechanism of FAN on OS and whether it can inhibit HCC by mediating OS are still unclear.

This paper aims to explore the effectiveness of FAN in preventing HCC via regulating OS and identify the underlying molecular mechanisms.

We used the primary HCC mouse model and hepatoma cell line to explore the suppressive effect of FAN on hepatocarcinogenesis. To study the role of ROS in the anti-hepatocarcinoma effect of FAN in cell model and mouse model. The mechanism of FAN-induced nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation was studied through various techniques, including generation of Nrf2 and tripartite motif containing 7 (TRIM7) gene overexpressing or knockdown cell model, co-immunoprecipitation, immunohistochemistry and subcutaneous tumor xenograft models constructed by the stable TRIM7-overexpression HLE cells, etc. RESULTS: We showed that FAN significantly inhibited cell proliferation and hepatocarcinogenesis in HCC cells and primary HCC mouse model. The FAN-induced mitochondrial dysfunction promoted ROS accumulation, and using N-Acetylcysteine to clear ROS reversed the anti-HCC effects of FAN. We observed that FAN is capable of activating the Nrf2 pathway. This effect was thought to be due to the fact that, in response to the FAN-induced OS, the cancer cells created a feedback loop to stable Nrf2 via depressing the K48-linkage ubiquitination of it, which was caused by reduced binding of kelch-like ECH-associated protein 1 (Keap1) and Nrf2 and elevated TRIM7 expression. Indeed, overexpression of TRIM7 suppressed the anti-hepatocarcinoma effect of FAN.

The study determines the anti-liver cancer effect of FAN and first describes the positive regulatory effect of TRIM7 on Nrf2 signaling. We reveal that TRIM7/Nrf2 signaling served as a target of FAN-induced ROS accumulation in HCC, which helps to clarify the mechanism of action of FAN against HCC and provides a theoretical basis for FAN as an anti-cancer drug.

Promyelocytic leukemia protein (PML) nuclear bodies (NBs) are essential in regulating tumor suppression, antiviral response, inflammation, metabolism, aging, and other important life processes. The re-assembly of PML NBs might lead to an ~100% cure of acute promyelocytic leukemia. However, until now, the molecular mechanism underpinning PML NB biogenesis remains elusive due to the lack of structural information. In this study, we present the cryo-electron microscopy (cryo-EM) structure of the PML dimer at an overall resolution of 5.3 Å, encompassing the RING, B-box1/2 and part of the coiled-coil (RBCC) domains. The integrated approach, combining crosslinking and mass spectrometry (XL-MS) and functional analyses, enabled us to observe a unique folding event within the RBCC domains. The RING and B-box1/2 domains fold around the α3 helix, and the α6 helix serves as a pivotal interface for PML dimerization. More importantly, further characterizations of the cryo-EM structure in conjugation with AlphaFold2 prediction, XL-MS, and NB formation assays, help unveil an unprecedented octopus-like mechanism in NB assembly, wherein each CC helix of a PML dimer (PML dimer A) interacts with a CC helix from a neighboring PML dimer (PML dimer B) in an anti-parallel configuration, ultimately leading to the formation of a 2 µm membrane-less subcellular organelle.

One of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterized across human populations, and it is unclear how genetic and environmental variation contribute to AS. Here, we examine a set of 115 Indonesian samples from three traditional island populations spanning the genetic ancestry cline that characterizes Island Southeast Asia. We conduct a global AS analysis between islands to ascertain the degree of functionally significant AS events and their consequences. Using an event-based statistical model, we detected over 1,500 significant differential AS events across all comparisons. Additionally, we identify over 6,000 genetic variants associated with changes in splicing (splicing quantitative trait loci [sQTLs]), some of which are driven by Papuan-like genetic ancestry, and only show partial overlap with other publicly available sQTL datasets derived from other populations. Computational predictions of RNA binding activity reveal that a fraction of these sQTLs directly modulate the binding propensity of proteins involved in the splicing regulation of immune genes. Overall, these results contribute toward elucidating the role of genetic variation in shaping gene regulation in one of the most diverse regions in the world.

The proteostasis network and associated protein quality control (PQC) mechanisms ensure proteome functionality and are essential for cell survival. A distinctive feature of eukaryotic cells is their high degree of compartmentalization, requiring specific and adapted proteostasis networks for each compartment. The nucleus, essential for maintaining the integrity of genetic information and gene transcription, is one such compartment. While PQC mechanisms have been investigated for decades in the cytoplasm and the endoplasmic reticulum, our knowledge of nuclear PQC pathways is only emerging. Recent developments in the field have underscored the importance of spatially managing aberrant proteins within the nucleus. Upon proteotoxic stress, misfolded proteins and PQC effectors accumulate in various nuclear membrane-less organelles. Beyond bringing together effectors and substrates, the biophysical properties of these organelles allow novel PQC functions. In this review, we explore the specificity of the nuclear compartment, the effectors of the nuclear proteostasis network, and the PQC roles of nuclear membrane-less organelles in metazoans.

Metastasis, the dissemination of malignant cells from a primary tumor to secondary sites, poses a catastrophic burden to cancer treatment and is the predominant cause of mortality in cancer patients. Metastasis as one of the main aspects of cancer progression could be strongly under the influence of viral infections. In fact, viruses have been central to modern cancer research and are associated with a great number of cancer cases. Viral-encoded elements are involved in modulating essential pathways or specific targets that are implicated in different stages of metastasis. Considering the continuous emergence of new viruses and the establishment of their contribution to cancer progression, the warfare between viruses and cancer appears to be endless. Here we aimed to review the critical mechanism and pathways involved in cancer metastasis and the influence of viral machinery and various routes that viruses adopt to manipulate those pathways for their benefit.

Rho-associated coiled-coil kinase 2 (ROCK2) is classified as a member of the serine/threonine protein kinase family and has been identified as a key driver of the development of various forms of cancer. The cause of ROCK2's impact on acute myeloid leukemia (AML) is still unknown. We found that ROCK2 expression was higher in AML patients, leading to lower complete response rates and worse overall survival. Additionally, ROCK2 expression was elevated in the doxorubicin-resistant leukemia cell line HL-60/ADM when compared to their individual parent cells. Moreover, the suppression or inhibition of ROCK2 leads to enhanced drug sensitivity in both AML cell lines and primary AML specimens, along with a notable decrease in downstream signaling pathways. Furthermore, the suppression of ROCK2 caused disruption of cellular energy production pathways by directly affecting the functionality of proteins within the mitochondrial electron transport chain. Finally, we discovered that TRIM26, a specific E3 ligase, is capable of ubiquitylating ROCK2, and the upregulation of TRIM26 within HL-60/ADM cells resulted in heightened sensitivity to the drug and reduced resistance. Thus, our study presents a new strategy for overcoming drug resistance in AML through targeting ROCK2/AKT/MAPK signaling pathway.

Esophageal squamous cell carcinoma (ESCC) is a common fatal malignant tumor of the digestive tract; however, its pathogenic mechanism is unknown and lacks specific molecular diagnosis and treatment. Therefore, it is particularly important to identify new tumor biomarkers to enhance the early diagnosis and molecular-targeted therapy of ESCC. Here, we found that the E3 ubiquitin ligase Tripartitemotif-containing33 (TRIM33) is highly expressed in ESCC tissues and cell lines, and is associated with adverse clinical outcomes. We determined that TRIM33 drives aerobic glycolysis to promote tumor growth in vivo and in vitro. In terms of mechanism, TRIM33 binds to p53 to inhibit its stability and promote the expression of downstream glycolysis target genes GLUT1, HK2, PKM2, and LDHA. In addition, TRIM33 promotes the polyubiquitination of P53 K48-linked and proteasome degradation. Further studies have shown that the K351 site of P53 is the key site mediating the ubiquitination of P53 K48-linked to promote aerobic glycolysis in ESCC and tumor cell growth. Our results reveal that the TRIM33-P53 signal axis regulates glycolysis during ESCC and may provide a new perspective for the diagnosis and treatment of ESCC.

Bromodomain-containing protein 7 (BRD7) is downregulated and functions as a tumor suppressor in many types of cancers including breast cancer, and the dysregulation of BRD7 expression is closely related to the development and progression of breast cancer. Whereas little attention has been focused on the regulation of BRD7 protein levels in breast cancer, which needs to be further elucidated.

The protein stability of BRD7 in breast cancer cells and BRD7 protein level in breast cancer tissues was examined by Western Blotting. The potential E3 ubiquitin ligase proteins that interact with the BRD7 was screened by coimmunoprecipitation combined with mass spectrometry analysis in MDA-MB-231 cells. We proved the interaction between BRD7 and tripartite motif containing 28 (TRIM28) through Co-Immunoprecipitation (Co-IP) and immunofluorescence assays. Co-IP and ubiquitination assay were used to explore the specific binding domain between BRD7 and TRIM28 and the ubiquitination site of BRD7. The effects of TRIM28 on the BRD7 protein stability and ubiquitination level was investigated by qPCR, Western Blot and Co-IP assay. CCK-8 and clone formation assays were carried out to assess the effect of TRIM28 on proliferation ability of breast cancer ells. Transwell assay and wound healing assay were used to investigate the effect of TRIM28 on breast cancer cell invasion and migration. Flow cytometry was used to detect the effect of TRIM28 on cell cycle and apoptosis of breast cancer cells. In addition, we confirmed effect of TRIM28 on tumor growth and metastasis by xenograft and metastatic mouse models. We designed some recovery assays to explore the role of recovery BRD7 in TRIM28-mediated promotion of malignant progression of breast cancer in vivo and in vitro. Finally, the clinical significance of TRIM28 and BRD7 was proved by immunohistochemistry.

In this study, we demonstrated that BRD7 was an unstable protein and might be regulated by ubiquitination in breast cancer; furthermore, we found that the Coiled-Coil region of TRIM28 could directly bind to N-terminal of BRD7, and TRIM28 mediates BRD7 ubiquitination and degradation dependent on K21 by acting as a potential E3 ubiquitin ligase. Moreover, TRIM28 promoted cell proliferation, migration, invasion, xenograft tumor growth and metastasis, thus playing an oncogenic role in breast cancer. Furthermore, the restoration of BRD7 expression in breast cancer significantly reversed the promotional effects of TRIM28 on malignant progression both in vitro and in vivo. In addition, TRIM28 was highly expressed in the biopsy tissues of breast cancer, and its expression was negatively correlated with BRD7 expression and positively correlated with TNM stage and poor prognosis of BC patients.

Our findings provide a novel mechanism by which TRIM28 significantly facilitates BRD7 ubiquitination and degradation, thus promoting breast cancer malignant progression. Targeting the TRIM28/BRD7 axis might be a novel potential strategy for the clinical diagnosis and treatment of breast cancer.

TRIM family proteins are widely found in multicellular organisms and are involved in a wide range of life activities, and also act as crucial regulators in the antiviral natural immune response. This study aimed to reveal the molecular mechanism of rainbow trout TRIM protein in the anti-IHNV process. The results demonstrated that 99.1 % homology between the rainbow trout and the chinook salmon (Oncorhynchus tshawytscha) TRIM32. When rainbow trout were infected with IHNV, the TRIM32 was highly expressed in the gill, spleen, kidney and blood. Meanwhile, rainbow trout TRIM32 has E3 ubiquitin ligase activity and undergoes K29-linked polyubiquitination modifications dependent on the RING structural domain was determined by immunoprecipitation. TRIM32 could interact with the NV protein of IHNV and degrade NV protein through the ubiquitin-proteasome pathway, and was also able to activate NF-κB transcription, thereby inhibiting the replication of IHNV. Moreover, the results of the animal studies showed that the survival rate of rainbow trout overexpressing TRIM32 was 70.2 % which was significantly higher than that of the control group, and stimulating the body to produce high levels of IgM when the host was infected with the virus. In addition, TRIM32 can activate the NF-κB signalling pathway and participate in the antiviral natural immune response. The results of this study will help us to understand the molecular mechanism of TRIM protein resistance in rainbow trout, and provide new ideas for disease resistance breeding, vaccine development and immune formulation development in rainbow trout.

Tripartite motif-containing 37 (TRIM37) is reportedly a key member of the superfamily of TRIM proteins. Emerging evidence underscores the close association between dysregulated TRIM37 expression and the progression of various human malignancies. However, the precise biological functions and regulatory mechanisms of TRIM37 remain elusive. This study aimed to elucidate the impact of TRIM37 on the chemotherapy sensitivity of renal cell carcinoma (RCC) and uncover its specific molecular regulatory role. Using RT-qPCR and western blot assays, we assessed TRIM37 expression in both RCC patients and RCC cells. Through in vitro and in vivo experiments, we investigated the effects of TRIM37 silencing and overexpression on RCC cell proliferation, stemness capacity, and chemotherapy sensitivity using colony formation and sphere formation assays. Additionally, a co-immunoprecipitation (Co-IP) experiment was conducted to explore putative interacting proteins. Our results revealed elevated TRIM37 expression in both RCC patient tumor tissues and RCC cells. Functional experiments consistently demonstrated that TRIM37 silencing reduced proliferation and stemness capacity while enhancing chemotherapy sensitivity in RCC cells. Furthermore, we discovered that TRIM37 mediates the degradation of SMARCC2 via ubiquitin-proteasome pathways, thereby further activating the Wnt signaling pathway. In conclusion, this study not only sheds light on the biological role of TRIM37 in RCC progression but also identifies a potential molecular target for therapeutic intervention in RCC patients.

Skp1-CUL1-ROC1-F-box E3 ubiquitin ligases' main component S-phase kinase-associated protein 2 (Skp2) is responsible for specifically recognizing ubiquitination-modified substrates to be degraded such as p27 and p21 in the case of binding with adaptor protein Cks1. Pharmacological inhibition of Skp2 has exhibited promising antitumor activity. Herein, we present the design and optimization of a series of [1,2,4]triazolo[1,5-a]pyrimidine-based small molecules targeting Skp2. Among them, E35 demonstrated excellent inhibitory activities against the binding of Skp2-Cks1. In addition, compound E35 significantly inhibited colony formation and migration, as well as arrested the cell cycle at the S-phase. Mechanistically, compound E35 markedly decreased the expression of Skp2, as well as increased the expression of its substrates p21 and p27. Furthermore, compound E35 showed an obvious inhibitory effect on MGC-803 xenograft mice without obvious toxicity. All of these results suggest that compound E35 might be a valuable lead compound for antitumor agents targeting Skp2.