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The healthy progression and termination of pregnancy depend critically upon embryo development, acquisition of uterine receptivity, implantation, and decidualization during the peri-implantation period. Sumoylation is a post-translational modification that affects the stability, transcriptional activity, and cellular localization of proteins. In our study, we investigated the localization and expression of SUMO1 (small ubiquitin-like modifier), SENP1 (sentrin-specific protease 1), and UBC9 (SUMO-conjugated enzyme UBC9), members of the sumoylation mechanism, in the mouse uterus and implantation sites during the peri-implantation period. Localization and expressions of SUMO1, SENP1, and UBC9 were determined by immunohistochemistry and Western blot, respectively. Estrogen (E 2 ) and progesterone (P 4 ) levels were measured by ELISA. SUMO1 was at the highest level in the luminal and gland epithelium and stroma on the 5th day of pregnancy compared to other pregnancy days. SENP1 was high on the 4th but low on the 5th day of pregnancy. On the 6th and 8th days of pregnancy, expressions of SUMO1 and SENP1 were decreased, while the amount of UBC9 was similar to other days of pregnancy. According to ELISA, E 2 reached its highest level on the 4th day of pregnancy, and P 4 reached its highest level on the 8th day of pregnancy. SUMO1, SENP1, and UBC9 are expressed at different levels in the uterus and implantation sites during early pregnancy. Our findings suggest that the sumoylation mechanism may play a role in the implantation and decidualization processes of mice.

SUMOylation is a reversible post-translational modification which has emerged as a crucial molecular regulatory mechanism, involved in the regulation of DNA damage repair, immune responses, carcinogenesis, cell cycle progression and apoptosis. Four SUMO isoforms have been identified, which are SUMO1, SUMO2/3 and SUMO4. The small ubiquitin-like modifier (SUMO) pathway is conserved in all eukaryotes and plays pivotal roles in the regulation of gene expression, cellular signaling and the maintenance of genomic integrity. The SUMO catalytic cycle includes maturation, activation, conjugation, ligation and de-modification. The dysregulation of the SUMO system is associated with a number of diseases, particularly cancer. SUMOylation is widely involved in carcinogenesis, DNA damage response, cancer cell proliferation, metastasis and apoptosis. SUMO can be used as a potential therapeutic target for cancer. In this review, we briefly outline the basic concepts of the SUMO system and summarize the involvement of SUMO proteins in cancer cells in order to better understand the role of SUMO in human disease.

Osteoarthritis (OA) is a prevalent and debilitating joint disease in older adults with a complex etiology. We investigated the role of SUMOylation, a post-translational modification, in OA pathogenesis, focusing on the mitochondrial chaperone Prohibitin (PHB1) and the cartilage homeostasis transcription factor PITX1. We hypothesized that oxidative stress-induced SUMOylation promotes PHB1 nuclear accumulation, leading to PITX1 downregulation and contributing to OA development. Analysis of cartilage specimens from 27 OA patients and 4 healthy controls revealed an increased nuclear accumulation of PHB1 in OA chondrocytes, accompanied by elevated levels of SUMO-1 and SUMO-2/3. Mechanistically, nuclear PHB1 interacted indirectly with SUMO-1 through a SUMO-interacting motif (SIM), and the deletion of this SIM prevented PHB1 nuclear trapping in OA cells. Furthermore, the SUMO-conjugating enzyme E2 (UBC9) encoded by the UBE2I gene was upregulated in knee OA cartilage, and its overexpression in vitro enhanced PHB1 nuclear accumulation. Consistently, transgenic mice overexpressing the Ube2i gene exhibited increased UBC9 in their knee cartilage, resulting in Pitx1 downregulation and the emergence of an early OA-like phenotype in articular chondrocytes. Our findings uncover a novel role for UBC9-mediated SUMOylation in primary knee and hip OA. This pathway enhances PHB1 nuclear accumulation, contributing to PITX1 repression and subsequent OA development. These results underscore the importance of SUMOylation in OA pathogenesis and suggest potential molecular targets for early diagnosis and therapeutic intervention.

Colorectal cancer (CRC) is a highly prevalent and fatal malignancy, with incidence and mortality rates rising globally. While elevated UBC9 expression has been implicated in various cancers, its specific role in CRC remains poorly understood. This study aims to investigate the expression levels, prognostic significance, and functional roles of UBC9 in CRC. We assessed the expression and prognostic value of UBC9 mRNA and protein in colorectal cancer separately using multiple databases and immunohistochemical techniques. Additionally, in vitro functional assays and in vivo zebrafish tumor models were employed to elucidate the role of UBC9 in CRC cell proliferation, migration, invasion, and chemoresistance. UBC9 expression was significantly upregulated in CRC tissues. Elevated UBC9 levels were associated with poor prognosis in chemotherapy-treated CRC patients. Gene Set Enrichment Analysis revealed that pathways related to MYC targets, DNA repair, and oxidative stress response were enriched in groups with high UBC9 expression. Immune profiling indicated reduced infiltration of CD4+ memory-activated T cells and NK cells in tumors with elevated UBC9 levels. Functional assays demonstrated that UBC9 knockdown inhibited CRC cell proliferation, migration, and invasion, and sensitized cells to oxaliplatin, which was further validated using zebrafish xenograft models. UBC9 is crucial for CRC progression, genomic instability, and chemoresistance. It represents a potential prognostic biomarker and therapeutic target, particularly for enhancing chemotherapy efficacy in CRC patients.

Significance Currently there are no targeted therapies for KRAS mutant cancer. Our study uncovers a critical role of the small ubiquitin-like modifier (SUMO) E2 ligase Ubc9 in sustaining the transformation growth of KRAS mutant colorectal cancer cells, thus establishing a functional link between the SUMO pathway and the KRAS oncogene. SUMO ligases are poorly explored drug targets; our work suggests that targeting the SUMO pathway, and Ubc9 in particular, could be potentially useful for the treatment of KRAS mutant colorectal cancers. The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.

SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly–Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases.

Gastric cancer remains a leading cause of cancer-related mortality worldwide, characterized by poor prognosis due to its aggressive nature and high metastatic potential. While the E2-conjugating enzyme UBE2I (UBC9), essential for SUMOylation, has been implicated in various cancers, its precise role in gastric cancer remains poorly understood. In the study, we demonstrate significant UBC9 overexpression in gastric cancer tissues, which correlates with poor clinical outcomes. Functional analyses revealed that UBC9 knockdown significantly suppressed gastric cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas UBC9 overexpression enhanced these malignant phenotypes. Through integrated transcriptomic and proteomic analyses, we identified ATF2 (Activating Transcription Factor 2) as a crucial downstream effector of UBC9-mediated oncogenic signaling. The mechanistic relationship between these factors was confirmed as ATF2 knockdown substantially attenuated the oncogenic effects of UBC9 overexpression. This newly identified UBC9-ATF2 regulatory axis promotes gastric cancer progression by enhancing cellular proliferation and metastatic potential. Our findings establish UBC9 and ATF2 as promising prognostic biomarkers and potential therapeutic targets, suggesting that intervention in the UBC9-ATF2 axis may provide novel therapeutic strategies for inhibiting gastric cancer progression and improving patient outcomes.

Background Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons. UBC9 is related to the formation of several cancers. Nevertheless, the function of UBC9 in PD and the potential mechanisms are vague. Methods MPP⁺-induced SH-SY5Y cells and MPTP-treated C57BL/6 mice were applied to induce PD models. Cell viability, proliferation and apoptosis were measured using CCK-8, EdU and Annexin V/PI staining, respectively. JC-1 staining and fluorescent probes DCFH-DA were employed to measure mitochondrial membrane potential and ROS production. The SOD, GSH and MDA content were determined by the commercially kits. SUMOylation of PINK1 were predicted by SUMOplot and verified by co-IP/Western blot. Mitophagy-related proteins, SUMO enzymes, and TH were analyzed by qRT-PCR/Western blot. LC3 expression was detected via immunofluorescence staining. Transmission electron microscopy was performed to detect autophagy. MPTP-induced brain injury was evaluated using Nissl staining, IHC and TUNEL assay. Motor function was observed via open field test and pole test. Results PINK1 and UBC9 were low-expressed in MPP + -induced SH-SY5Y cells. UBC9 mediated PINK1 SUMOylation. UBC9 overexpression promoted cell viability and reduced cells apoptosis in MPP + -stimulated SH-SY5Y cells, which was reversed after PINK1 silence or CsA treatment. Moreover, UBC9 overexpression counteracted MPP + -induced mitophagy, and oxidative stress. However, these findings were reversed by CsA or PINK1 silencing. PINK1 bound SUMO1 at the K522, K363 and K193 sites, further regulating cells viability and apoptosis. In MPTP-treated mice, UBC9 overexpression alleviated mitochondrial dysfunction and motor deficits via PINK1 SUMOylation. Conclusion UBC9 mediated mitophagy to attenuate MPP + /MPTP-induced neurotoxicity and oxidative stress by regulating PINK1 SUMOylation, suggesting that UBC9 may play a preventive role in PD progression. Highlights UBC9 enhanced PINK1 stability by promoting SUMOylation of PINK1 at the K522R/K363R position. UBC9 regulated MPP + -induced SH-SY5Y cells proliferation and apoptosis via PINK1. UBC9 alleviated MPTP-induced motor dysfunction and oxidative stress via PINK1-mediated mitophagy. Graphical abstract

Background Hepatic ischaemia/reperfusion (I/R) injury poses a common clinical dilemma encountered during liver transplantation (LT), characterised by substantial cellular death and inflammation reactions. Ubc9, the sole E2 conjugating enzyme of SUMOylation, has long been recognised to regulate diverse biological and pathological processes. However, its impact on I/R‐induced liver damage is yet to be elucidated. Methods The expression levels of UBC9 in patients undergoing LT were analysed. Hepatocyte‐specific Ubc9‐deficient or transgenic mice were utilised in an in vivo model of hepatic I/R, alongside in vitro experiments that employed hypoxia/reoxygenation stimulation. The investigation focused on Ubc9's role in liver damage due to I/R and the underlying mechanisms through a range of phenotypic analyses and biological techniques. Results Herein, we found that hepatic tissues from patients with LT are featured by a significant downregulation of UBC9 expression. Studies in 68 donor hepatic biopsies further demonstrated a negative correlation between UBC9 expression and liver injury in patients with LT. Similarly, murine liver I/R was coupled with an obvious decrease in Ubc9 expression. Hepatocyte deficient in Ubc9 exacerbated liver injury in liver I/R, while Ubc9‐overexpression showed the opposite phenotype. Mechanistically, Ubc9‐mediated SUMOylation of Ninj1 at lysine K103 inhibited its membrane localisation and damage‐associated molecular patterns (DAMPs) release in hepatocytes, subsequently inhibited nuclear factor‐kappa B (NF‐κB) signalling in macrophages and curtailing inflammatory cytokines production. Conclusions These findings further suggest that Ubc9‐mediated SUMOylation of Ninj1 at lysine K103 may represent a potential therapeutic strategy for safeguarding the liver against I/R injury in clinical settings. Key points Ubc9 expression is downregulated in hepatocytes during hepatic ischaemia/reperfusion (I/R) injury. Higher UBC9 expression is associated with improved post‐liver transplantation (LT) liver function. Ubc9 ameliorates liver damage and inflammation responses in hepatic I/R injury. Ubc9‐mediated Ninj1 SUMOylation at K103 is essential for regulating the subcellular distribution of Ninj1. Ubc9 inhibits the release of hepatocyte‐derived damage‐associated molecular patterns (DAMPs) in a Ninj1 K103 SUMOylation‐dependent manner. Ubc9 expression is downregulated in hepatocytes during hepatic I/R injury. Higher UBC9 expression is associated with improved post‐LT liver function. Ubc9 ameliorates liver damage and inflammation responses in hepatic I/R injury. Ubc9‐mediated Ninj1 SUMOylation at K103 is essential for regulating the subcellular distribution of Ninj1. Ubc9 inhibits the release of hepatocyte‐derived DAMPs in a Ninj1 K103 SUMOylation‐dependent manner.

Retinal vasculopathies pose a devastating threat to human health. While anti‐VEGF therapy situates the first‐line treatment for patients, the clinical efficacy is limited by suboptimal response and potential risks raised by long‐term high‐dosage use. Neurovascular unit uncoupling is recognized as a key mechanism contributing to pathological neovascularization, yet how immune components get involved is less appreciated. Here, it is reported that SUMOylation modulates the pro‐angiogenic capacity of macrophage, and inhibition of the SUMO‐conjugating enzyme UBC9 synergizes with anti‐VEGF therapy in preclinical models. Diabetic human retinal mononuclear phagocytes (MNPs) overexpress UBC9. Genetic ablation of UBC9 in MNPs compromises the crosstalk with endothelial cells by reducing Vegfa splicing isoforms, including Vegf120, Vegf144, Vegf164, and Vegf188. Mechanistically, hypoxia facilitates the SUMOylation of fused in sarcoma (FUS) protein at lysine residues K327 and K502. Mutation of the SUMOylation sites enhances FUS binding to the Vegfa 3′‐untranslated region (3′UTR), leading to mRNA destabilization and decreased VEGFA production. Intravitreal administration of anti‐VEGF elevates UBC9 whereas Ubc9 siRNA‐liposomes alleviates retinal vascular leakage and choroidal neovascularization, and a better therapeutic efficacy is yielded when combining with anti‐VEGF therapy. Taken together, this study highlights a novel approach for treating retinal vascular diseases by modulating the MNPs‐endothelial cell interplay. During ischemic retinopathy/retinal vasculopathy, UBC9‐mediated SUMOylation in retinal macrophages enhances their pro‐angiogenic capacity via hypoxia‐induced SUMOylation of FUS at K327/K502. This modification suppresses FUS binding to the Vegfa mRNA 3’UTR, stabilizing transcripts and facilitating VEGFA production. Targeting UBC9 inhibition can serve as a potential therapeutic strategy for retinal vasculopathy, with a combination of anti‐VEGF therapy demonstrating promising synergistic effects.