• Cell cycle
• Malignancy
• Oncogenesis
• RANBP2
• SUMOylation

• United States-Israel Binational Science Foundation
• European Research Council

• SUMOylation
• diabetes mellitus
• immune
• inflammation
• posttranslation modification
• signaling pathway

• Humans
• Sumoylation/immunology
• Animals
• Signal Transduction/immunology
• Protein Processing, Post-Translational
• Diabetes Mellitus/immunology
• Diabetes Mellitus/metabolism
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Cellular Microenvironment/immunology
• Diabetes Mellitus, Type 2/immunology
• Diabetes Mellitus, Type 2/metabolism

• SUMO inhibitor
• SUMOylation
• TAK-981
• drug sensitivity
• therapeutic targets
• thyroid cancer

• 23SHS05200 Shanghai Innovation Medical Device Application Demonstration Project 2023

• Colorectal cancer
• Gut
• Inflammatory bowel diseases
• Pathology
• Physiology
• SUMOylation

• Humans
• Sumoylation
• Animals
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/pathology

• 22JR11RA066 Natural Science Foundation of Gansu Province
• 22JR11RA066 Natural Science Foundation of Gansu Province
• 22JR11RA066 Natural Science Foundation of Gansu Province
• CY2021-QN-B14 Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital
• CY2021-QN-B14 Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital
• CY2021-QN-B14 Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital
• 2022B-061 Education Science and Technology Innovation Project of Gansu Province

• SUMOylation
• USP36
• deubiquitination
• ribosome biogenesis
• ubiquitin

• R01 CA262104 NCI NIH HHS
• R01 GM130604 NIGMS NIH HHS

• Immune cells
• SENPs
• SUMOylation
• Ubc9

• Humans
• Animals
• Mice
• Ubiquitin-Conjugating Enzymes/genetics
• Ubiquitin-Conjugating Enzymes/metabolism
• Small Ubiquitin-Related Modifier Proteins/genetics
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Sumoylation
• Cysteine/genetics
• Ubiquitins/metabolism
• Ubiquitin/metabolism
• Neoplasms/genetics

• 112-2320-B001-026-MY3 National Science and Technology Council
• NHRI-EX108-10835SI National Health Research Institutes
• AS-VTA-112-01 Academia Sinica
• Genomics Research Center, Academia Sinica
• Taiwan Bio-Development Foundation

• Affinity chromatography
• Nanobody
• Protein purification
• Sumo

• Humans
• Small Ubiquitin-Related Modifier Proteins/chemistry
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Single-Domain Antibodies/metabolism
• SUMO-1 Protein
• Peptides
• Saccharomyces cerevisiae/metabolism
• Chromatography, Affinity/methods
• Recombinant Fusion Proteins

• SENP1
• anticancer
• drug discovery
• inhibitors

• SUMOylation
• components
• pathogenesis
• rheumatoid arthritis
• small ubiquitin-like modifier (SUMO)
• treatment

SUMO modification is a vital post-translational regulation process in eukaryotes, in which the SUMO protease is responsible for the maturation of the SUMO precursor and the deconjugation of the SUMO protein from modified proteins by accurately cleaving behind the C-terminal Gly–Gly motif. To promote the understanding of the high specificity of the SUMO protease against the SUMO protein as well as to clarify whether the conserved Gly–Gly motif is strictly required for the processing of the SUMO precursor, we systematically profiled the specificity of the S. cerevisiae SUMO protease (Ulp1) on Smt3 at the P2–P1↓P1’ (Gly–Gly↓Ala) position using the YESS–PSSC system. Our results demonstrated that Ulp1 was able to cleave Gly–Gly↓ motif-mutated substrates, indicating that the diglycine motif is not strictly required for Ulp1 cleavage. A structural-modeling analysis indicated that it is the special tapered active pocket of Ulp1 conferred the selectivity of small residues at the P1–P2 position of Smt3, such as Gly, Ala, Ser and Cys, and only which can smoothly deliver the scissile bond into the active site for cleavage. Meanwhile, the P1’ position Ala of Smt3 was found to play a vital role in maintaining Ulp1’s precise cleavage after the Gly–Gly motif and replacing Ala with Gly in this position could expand Ulp1 inclusivity against the P1 and P2 position residues of Smt3. All in all, our studies advanced the traditional knowledge of the SUMO protein, which may provide potential directions for the drug discovery of abnormal SUMOylation-related diseases.

• Saccharomyces cerevisiae/genetics
• Saccharomyces cerevisiae/metabolism
• Substrate Specificity
• Saccharomyces cerevisiae Proteins/metabolism
• Small Ubiquitin-Related Modifier Proteins/genetics
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Peptide Hydrolases/metabolism
• Glycylglycine/metabolism
• Cysteine Endopeptidases/metabolism
• SUMO-1 Protein/metabolism

Discoveries made in the nematode Caenorhabditis elegans revealed that aging is under genetic control. Since these transformative initial studies, C. elegans has become a premier model system for aging research. Critically, the genes, pathways, and processes that have fundamental roles in organismal aging are deeply conserved throughout evolution. This conservation has led to a wealth of knowledge regarding both the processes that influence aging and the identification of molecular and cellular hallmarks that play a causative role in the physiological decline of organisms. One key feature of age-associated decline is the failure of mechanisms that maintain proper function of the proteome (proteostasis). Here we highlight components of the proteostatic network that act to maintain the proteome and how this network integrates into major longevity signaling pathways. We focus in depth on the heat shock transcription factor 1 (HSF1), the central regulator of gene expression for proteins that maintain the cytosolic and nuclear proteomes, and a key effector of longevity signals.

• R21 AG064519 NIA NIH HHS
• RF1 AG062593 NIA NIH HHS
• National Institute on Aging

Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the cellular level, sumoylation functions as a key regulator of transcription, nuclear integrity, proliferation, senescence, lineage commitment and stemness. A growing number of prokaryotic and viral proteins are also emerging as prime sumoylation targets, highlighting the role of this modification during infection and in immune processes. Sumoylation also oversees epigenetic processes. Accordingly, at the physiological level, it acts as a crucial regulator of development. Yet, perhaps the most prominent function of sumoylation, from mammals to plants, is its role in orchestrating organismal responses to environmental stresses ranging from hypoxia to nutrient stress. Consequently, a growing list of pathological conditions, including cancer and neurodegeneration, have now been unambiguously associated with either aberrant sumoylation of specific proteins and/or dysregulated global cellular sumoylation. Therapeutic enforcement of sumoylation can also accomplish remarkable clinical responses in various diseases, notably acute promyelocytic leukemia (APL). In this review, we will discuss how this modification is emerging as a novel drug target, highlighting from the perspective of translational medicine, its potential and limitations.

• peptides
• photoredox catalysis
• radicals
• reaction mechanisms

• Catalysis
• Peptides/chemistry
• Oxidation-Reduction
• Photochemical Processes
• Succinates/chemistry
• Molecular Structure

• 22077080 National Natural Science Foundation of China
• 21907064 National Natural Science Foundation of China
• 22107068 National Natural Science Foundation of China
• This funding number will be updated by NSFC in the end of the year National Natural Science Foundation of China

Post-translational modification by SUMO (small ubiquitin-like modifier) proteins has been shown to regulate a variety of functions of proteins, including protein stability, chromatin organization, transcription, DNA repair, subcellular localization, protein–protein interactions, and protein homeostasis. SENP (sentrin/SUMO-specific protease) regulates precursor processing and deconjugation of SUMO to control cellular mechanisms. SENP3, which is one of the SENP family members, deconjugates target proteins to alter protein modification. The effect of modification via SUMO and SENP3 is crucial to maintain the balance of SUMOylation and guarantee normal protein function and cellular activities. SENP3 acts as an oxidative stress-responsive molecule under physiological conditions. Under pathological conditions, if the SUMOylation process of proteins is affected by variations in SENP3 levels, it will cause a cellular reaction and ultimately lead to abnormal cellular activities and the occurrence and development of human diseases, including cardiovascular diseases, neurological diseases, and various cancers. In this review, we summarized the most recent advances concerning the critical roles of SENP3 in normal physiological and pathological conditions as well as the potential clinical implications in various diseases. Targeting SENP3 alone or in combination with current therapies might provide powerful targeted therapeutic strategies for the treatment of these diseases.

• SENP3
• SUMOylation
• cancer
• cardiovascular disease
• neurological disease

Sumoylation is the covalent attachment of the small ubiquitin-related modifier (SUMO) to a vast variety of proteins in order to modulate their function. Sumoylation has emerged as an important modification with a regulatory role in the cellular response to different types of stress including osmotic, hypoxic and oxidative stress. Hypoxia can occur under physiological or pathological conditions, such as ischemia and cancer, as a result of an oxygen imbalance caused by low supply and/or increased consumption. The hypoxia inducible factors (HIFs), and the proteins that regulate their fate, are critical molecular mediators of the response to hypoxia and modulate procedures such as glucose and lipid metabolism, angiogenesis, erythropoiesis and, in the case of cancer, tumor progression and metastasis. Here, we provide an overview of the sumoylation-dependent mechanisms that are activated under hypoxia and the way they influence key players of the hypoxic response pathway. As hypoxia is a hallmark of many diseases, understanding the interrelated connections between the SUMO and the hypoxic signaling pathways can open the way for future molecular therapeutic interventions.

• HIF
• HIF-1α
• SUMO
• hypoxia
• oxygen homeostasis
• sumoylation

• Cardiovascular diseases
• Post-translational modification
• SUMO
• SUMOylation

• Cardiovascular System/metabolism
• Humans
• Protein Processing, Post-Translational
• Small Ubiquitin-Related Modifier Proteins/metabolism

• Deutsches Zentrum für Herz-Kreislaufforschung

• SUMO
• Sentrin
• biochemistry
• cancer
• heart
• physiology

•

Sepsis infects more than 48.9 million people world-wide, with 19.7 million deaths.

Cytokine storm generates during various systemic acute infections, including sepsis and current pandemic called COVID-19 (severe) causing devastating inflammatory conditions, which include multi-organ failure or multi-organ dysfunction syndrome (MODS) and death of the patient. Toll-like receptors (TLRs) are one of the major pattern recognition receptors (PRRs) expressed by immune cells as well as non-immune cells, including neurons, which play a crucial role in generating cytokine storm. They recognize microbial-associated molecular patterns (MAMPs, expressed by pathogens) and damage or death-associate molecular patterns (DAMPs; released and/expressed by damaged/killed host cells). Upon recognition of MAMPs and DAMPs, TLRs activate downstream signaling pathways releasing several pro-inflammatory mediators [cytokines, chemokines, interferons, and reactive oxygen and nitrogen species (ROS or RNS)], which cause acute inflammation meant to control the pathogen and repair the damage. Induction of an exaggerated response due to genetic makeup of the host and/or persistence of the pathogen due to its evasion mechanisms may lead to severe systemic inflammatory condition called sepsis in response to the generation of cytokine storm and organ dysfunction. The activation of TLR-induced inflammatory response is hardwired to the induction of several negative feedback mechanisms that come into play to conclude the response and maintain immune homeostasis. This state-of-the-art review describes the importance of TLR signaling in the onset of the sepsis-associated cytokine storm and discusses various host-derived endogenous negative regulators of TLR signaling pathways. The subject is very important as there is a vast array of genes and processes implicated in these negative feedback mechanisms. These molecules and mechanisms can be targeted for developing novel therapeutic drugs for cytokine storm-associated diseases, including sepsis, severe COVID-19, and other inflammatory diseases, where TLR-signaling plays a significant role.

• Cytokine storm
• Cytokines
• Innate Immunity
• PAMPs
• Sepsis
• TLRs

• IQ motif‐containing GTPase‐activating protein 1
• acetylcholine
• coronary spastic angina
• p122RhoGTPase‐activating protein (GAP)/deleted in liver cancer‐1
• phospholipase C

• Uehara Memorial Foundation

• Deubiquitinating enzymes
• MYC
• SUMO
• SUMOylation
• Ubiquitination
• deSUMOylating enzymes

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.

• SUMO1-3
• SUMOylation
• glioblastoma (GBM)
• post-translational modifications (PTMs)

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Brain/drug effects
• Brain/metabolism
• Brain/pathology
• Brain Neoplasms/drug therapy
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Glioblastoma/drug therapy
• Glioblastoma/metabolism
• Glioblastoma/pathology
• Humans
• Molecular Targeted Therapy/methods
• Protein Processing, Post-Translational/drug effects
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Sumoylation/drug effects

• P30 CA013148 NCI NIH HHS

SUMOylation is a kind of important post-translational modification. In the present study, we identified 10 key genes involved in SUMOylation and deSUMOylation (sumo1, sumo2, sumo3, sae1, uba2, ubc9, pias1, senp1, senp2, and senp3) in yellow catfish Pelteobagrus fulvidraco, investigated their tissue expression patterns and transcriptional responses to carbohydrate addition both in vivo and in vitro. All of these members shared similar domains to their orthologous genes of other vertebrates. Their mRNAs were widely expressed in all the tested tissues, but at variable levels. Dietary carbohydrate levels differentially influenced the mRNA levels of these genes in liver, muscle, testis, and ovary of yellow catfish. Their mRNA levels in primary hepatocytes were differentially responsive to glucose addition. Our study would contribute to our understanding into the molecular basis of SUMOylation modification and into the potential SUMOylation function in the carbohydrate utilization in fish.

• SUMOylation
• carbohydrate
• fish
• molecular characterization
• transcriptional responses

• gastric cancer
• gene expression
• junk DNA
• ncRNAs
• pseudogene

• Female
• Humans
• Male
• Pseudogenes
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology

• DNA Breaks, Double-Stranded
• DNA Repair
• Eukaryotic Cells/enzymology
• Eukaryotic Cells/physiology
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Sumoylation
• Ubiquitin/metabolism

• 19062 Cancer Research UK
• C8820/A19062 Cancer Research UK

• CRMP2
• NaV1.7
• SUMOylation
• X-ray crystallography
• post-translational modifications
• trafficking

Small Ubiquitin-like Modifier (SUMO) is a ∼10 kDa peptide that can be post-translationally added to a lysine (K) on a target protein to facilitate protein–protein interactions. Recent studies have found that SUMOylation can be regulated in an activity-dependent manner and that ion channel SUMOylation can alter the biophysical properties and surface expression of the channel. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel surface expression can be regulated in an activity-dependent manner through unknown processes. We hypothesized that SUMOylation might influence the surface expression of HCN2 channels. In this manuscript, we show that HCN2 channels are SUMOylated in the mouse brain. Baseline levels of SUMOylation were also observed for a GFP-tagged HCN2 channel stably expressed in Human embryonic kidney (Hek) cells. Elevating GFP-HCN2 channel SUMOylation above baseline in Hek cells led to an increase in surface expression that augmented the hyperpolarization-activated current (I_h) mediated by these channels. Increased SUMOylation did not alter I_h voltage-dependence or kinetics of activation. There are five predicted intracellular SUMOylation sites on HCN2. Site-directed mutagenesis indicated that more than one K on the GFP-HCN2 channel was SUMOylated. Enhancing SUMOylation at one of the five predicted sites, K669, led to the increase in surface expression and I_hG_max. The role of SUMOylation at additional sites is currently unknown. The SUMOylation site at K669 is also conserved in HCN1 channels. Aberrant SUMOylation has been linked to neurological diseases that also display alterations in HCN1 and HCN2 channel expression, such as seizures and Parkinson’s disease. This work is the first report that HCN channels can be SUMOylated and that this can regulate surface expression and I_h.

• HCN
• SUMO
• cyclic nucleotide binding domain
• hyperpolarization-activated cyclic nucleotide-gated channel
• ion channel
• trafficking

• SAE1/2
• SENP
• SUMO
• SUMO Ligases
• Ubc9

• Prognosis
• Prostate cancer
• Survival
• TRIM
• Tripartite motif

• Channelopathies
• Epilepsy
• Potassium channels
• SUMOylation
• Sudden death

• Death, Sudden/pathology
• Epilepsy/genetics
• Epilepsy/pathology
• Humans
• Neurons/metabolism
• Neurons/pathology
• Potassium Channels/genetics
• Potassium Channels/metabolism
• Protein Processing, Post-Translational/genetics
• Sumoylation/genetics

• PolySUMO chains
• RanGAP1
• SENPs
• SUMO
• SUMO precursors
• Sentrin/SUMO-specific proteases

DGCR8 (DiGeorge syndrome critical region gene 8) is essential for primary microRNA (pri-miRNA) processing in the cell nucleus. It specifically combines with Drosha, a nuclear RNase III enzyme, to form the Microprocessor complex (MC) that cleaves pri-miRNA to precursor miRNA (pre-miRNA), which is further processed to mature miRNA by Dicer, a cytoplasmic RNase III enzyme. Increasing evidences suggest that pri-/pre-miRNAs have direct functions in regulation of gene expression, however the underlying mechanism how it is fine-tuned remains unclear. Here we find that DGCR8 is modified by SUMO1 at the major site K⁷⁰⁷, which can be promoted by its ERK-activated phosphorylation. SUMOylation of DGCR8 enhances the protein stability by preventing the degradation via the ubiquitin proteasome pathway. More importantly, SUMOylation of DGCR8 does not alter its association with Drosha, the MC activity and miRNA biogenesis, but rather influences its affinity with pri-miRNAs. This altered affinity of DGCR8 with pri-miRNAs seems to control the direct functions of pri-miRNAs in recognition and repression of the target mRNAs, which is evidently linked to the DGCR8 function in regulation of tumorigenesis and cell migration. Collectively, our data suggest a novel mechanism that SUMOylation of DGCR8 controls direct functions of pri-miRNAs in gene silencing.

• Animals
• Carcinogenesis
• Cell Line
• Cell Movement
• Cells, Cultured
• Humans
• Lysine/metabolism
• Mice
• Mice, Nude
• MicroRNAs/metabolism
• Neoplasms/metabolism
• Neoplasms/physiopathology
• Phosphorylation
• Protein Stability
• RNA-Binding Proteins/chemistry
• RNA-Binding Proteins/metabolism
• SUMO-1 Protein/metabolism
• Sumoylation
• Ubiquitination

• Biomarker
• Biomedicine
• Disorders
• SUMO
• Therapeutic target

• Animals
• Cell Nucleus/metabolism
• Humans
• Neurons/cytology
• Neurons/metabolism
• Neurons/pathology
• Neurons/physiology
• Protein Processing, Post-Translational
• Sumoylation

• BB/K014358/1 Biotechnology and Biological Sciences Research Council
• MR/L003791/1 Medical Research Council

• Apoptosis/genetics
• Cell Proliferation
• Cyclin D1/genetics
• Cyclin D1/metabolism
• Eukaryotic Initiation Factor-4E/metabolism
• Eukaryotic Initiation Factor-4G/metabolism
• Gene Expression Regulation
• Genes, Reporter
• HCT116 Cells
• Humans
• Hydrazones/pharmacology
• Multiprotein Complexes/metabolism
• Protein Binding/drug effects
• Protein Biosynthesis
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism
• RNA Caps
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Small Ubiquitin-Related Modifier Proteins/genetics
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Thiazoles/pharmacology

• crystallin gene expression
• eye development
• transcription regulation

Myc-family proteins are key controllers of the metabolic and proliferative status of the cell, and are subjected to a complex network of regulatory events that guarantee their efficient and fast modulation by extracellular stimuli. Hence, unbalances in regulatory mechanisms leading to altered Myc levels or activities are often reported in cancer cells. Here we show that c- and N-Myc are conjugated to SUMO proteins at conserved lysines in their C-terminal domain. No obvious effects of SUMOylation were detected on bulk N-Myc stability or activities, including the regulation of transcription, proliferation or apoptosis. N-Myc SUMOylation could be induced by cellular stresses, such as heat shock and proteasome inhibition, and in all instances concerned a small fraction of the N-Myc protein. We surmise that, as shown for other substrates, SUMOylation may be part of a quality-control mechanism acting on misfolded Myc proteins.

• Amino Acid Sequence
• Animals
• Cell Line, Tumor
• Heat-Shock Response
• Humans
• Lysine/metabolism
• Mice
• Molecular Sequence Data
• Mutant Proteins/metabolism
• Proto-Oncogene Proteins c-myc/chemistry
• Proto-Oncogene Proteins c-myc/metabolism
• Small Ubiquitin-Related Modifier Proteins/metabolism
• Stress, Physiological
• Sumoylation

• Fibroblasts
• Rheumatoid Arthritis
• TNF-alpha

• Animals
• Arthritis, Rheumatoid/metabolism
• Fibroblasts/metabolism
• Humans
• Matrix Metalloproteinase 13/metabolism
• Matrix Metalloproteinase 3/metabolism
• Mice
• Mice, Transgenic
• NF-kappa B/physiology
• Osteoarthritis/metabolism
• Signal Transduction
• Small Ubiquitin-Related Modifier Proteins/physiology
• Synovial Membrane/cytology
• Synovial Membrane/metabolism
• Tumor Necrosis Factor-alpha/genetics
• Tumor Necrosis Factor-alpha/physiology
• Ubiquitins/physiology

• Bioluminescence Resonance Energy Transfer (BRET)
• Calorimetry
• E2 SUMO Conjugating Enzyme
• E3 SUMO Ligase
• Gene Regulation
• Nuclear Magnetic Resonance
• Phosphorylation
• Protein Complexes
• SUMO Interacting Motif
• Sumoylation

During the replication of human cytomegalovirus (HCMV) genome, the viral DNA polymerase subunit UL44 plays a key role, as by binding both DNA and the polymerase catalytic subunit it confers processivity to the holoenzyme. However, several lines of evidence suggest that UL44 might have additional roles during virus life cycle. To shed light on this, we searched for cellular partners of UL44 by yeast two-hybrid screenings. Intriguingly, we discovered the interaction of UL44 with Ubc9, an enzyme involved in the covalent conjugation of SUMO (Small Ubiquitin-related MOdifier) to cellular and viral proteins. We found that UL44 can be extensively sumoylated not only in a cell-free system and in transfected cells, but also in HCMV-infected cells, in which about 50% of the protein resulted to be modified at late times post-infection, when viral genome replication is accomplished. Mass spectrometry studies revealed that UL44 possesses multiple SUMO target sites, located throughout the protein. Remarkably, we observed that binding of UL44 to DNA greatly stimulates its sumoylation both in vitro and in vivo. In addition, we showed that overexpression of SUMO alters the intranuclear distribution of UL44 in HCMV-infected cells, and enhances both virus production and DNA replication, arguing for an important role for sumoylation in HCMV life cycle and UL44 function(s). These data report for the first time the sumoylation of a viral processivity factor and show that there is a functional interplay between the HCMV UL44 protein and the cellular sumoylation system.