Transcription factor IRF3-mediated type I interferon induction is essential for antiviral innate immunity.We identified the deSUMOylating enzyme Sentrin/SUMO-specific protease(SENP)2 as a negative regulator of virus-t...Transcription factor IRF3-mediated type I interferon induction is essential for antiviral innate immunity.We identified the deSUMOylating enzyme Sentrin/SUMO-specific protease(SENP)2 as a negative regulator of virus-triggered IFN-b induction.Overexpression of SENP2 caused IRF3 deSUMOylation,K48-linked ubiquitination,and degradation,whereas depletion of SENP2 had opposite effects.Both the SUMOylation and K48-linked ubiquitination of IRF3 occurred at lysines 70 and 87,and these processes are competitive.The level of virus-triggered IFN-b was markedly up-regulated and viral replication was reduced in SENP2-deficient cells comparing with wild-type controls.Our findings suggest that SENP2 regulates antiviral innate immunity by deSUMOylating IRF3 and conditioning it for ubiquitination and degradation,and provide an example of cross-talk between the ubiquitin and SUMO pathways in innate immunity.展开更多
Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing ...Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.展开更多
One major function of adipocytes is to store excess energy in the form of triglycerides. Insufficient adipose lipid storage is asso- ciated with many pathological conditions including hyperlipidemia, insulin resistanc...One major function of adipocytes is to store excess energy in the form of triglycerides. Insufficient adipose lipid storage is asso- ciated with many pathological conditions including hyperlipidemia, insulin resistance, and type 2 diabetes. In this study, we observed the overexpression of SUMO-specific protease 2 （Senp2） in adipose tissues during obesity. Adipocyte 5enp2 deficiency resulted in less adipose lipid storage accompanied by an ectopic fat accumulation and insulin resistance under high-fat diet feeding. We further found that SET domain bifurcated 1 （Setdbl） was a SUMOylated protein and that SUMOylation promoted Setdbl occupancy on the promoter locus of Pparg and Cebpa genes to suppress their expressions by H3Kgme3. Senp2 could suppress Setdbl function by de-SUMOylation. In adipocyte 5enp2-deficiency mice, accumulation of the SUMOylated Setdbl suppressed the expression of Pparg and Cebpo genes as welt as lipid metabolism-related target genes, which would decrease the ability of lipid storage in adipocytes. These results revealed the crucial role of Senp2-Setdbl axis in controlling adipose lipid storage.展开更多
目的构建体外去SUMO化系统用于药物筛选。方法大肠杆菌表达人Senp2催化活性结构域即Senp2C和SUMO1化的RanGAP1△C。结果 Ni 2+柱纯化获得有活力的酶Senp2C和底物蛋白质即RanGAP1△C-SUMO1。结论建立体外去SUMO化系统,可筛选影响去SUMO...目的构建体外去SUMO化系统用于药物筛选。方法大肠杆菌表达人Senp2催化活性结构域即Senp2C和SUMO1化的RanGAP1△C。结果 Ni 2+柱纯化获得有活力的酶Senp2C和底物蛋白质即RanGAP1△C-SUMO1。结论建立体外去SUMO化系统,可筛选影响去SUMO化活性的药物。展开更多
基金supported by the grants from the National Natural Science Foundation of China (30921001 and 91029302).
文摘Transcription factor IRF3-mediated type I interferon induction is essential for antiviral innate immunity.We identified the deSUMOylating enzyme Sentrin/SUMO-specific protease(SENP)2 as a negative regulator of virus-triggered IFN-b induction.Overexpression of SENP2 caused IRF3 deSUMOylation,K48-linked ubiquitination,and degradation,whereas depletion of SENP2 had opposite effects.Both the SUMOylation and K48-linked ubiquitination of IRF3 occurred at lysines 70 and 87,and these processes are competitive.The level of virus-triggered IFN-b was markedly up-regulated and viral replication was reduced in SENP2-deficient cells comparing with wild-type controls.Our findings suggest that SENP2 regulates antiviral innate immunity by deSUMOylating IRF3 and conditioning it for ubiquitination and degradation,and provide an example of cross-talk between the ubiquitin and SUMO pathways in innate immunity.
基金supported by National Key Research and Development Program of China(2021YFB3800800)to Di Chen and Liping Tongsupported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342 and 82250710174)to Di Chen+1 种基金grant(82302757)to Ke Lusupported by SIAT Innovation Program for Excellent Young Researchers.
文摘Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.
基金This work was supported by grants from the National Natural Science Foundation of China （91019021 and 81430069 to J.C.）, the National Basic Research Program of China （973 Program） （2013CB910902 to J.C.）, Shanghai Committee of Science and Technology （15ZR1424500 to T.W. and 15140904300）, Shanghai Municipal Education Commission （ZZjdyx15003 to T.W. and 2017-01-07-00-01-E00050 to J.C.）, and Shanghai Jiao Tong University School of Medicine （14XJ10001 to T.W.）.
文摘One major function of adipocytes is to store excess energy in the form of triglycerides. Insufficient adipose lipid storage is asso- ciated with many pathological conditions including hyperlipidemia, insulin resistance, and type 2 diabetes. In this study, we observed the overexpression of SUMO-specific protease 2 （Senp2） in adipose tissues during obesity. Adipocyte 5enp2 deficiency resulted in less adipose lipid storage accompanied by an ectopic fat accumulation and insulin resistance under high-fat diet feeding. We further found that SET domain bifurcated 1 （Setdbl） was a SUMOylated protein and that SUMOylation promoted Setdbl occupancy on the promoter locus of Pparg and Cebpa genes to suppress their expressions by H3Kgme3. Senp2 could suppress Setdbl function by de-SUMOylation. In adipocyte 5enp2-deficiency mice, accumulation of the SUMOylated Setdbl suppressed the expression of Pparg and Cebpo genes as welt as lipid metabolism-related target genes, which would decrease the ability of lipid storage in adipocytes. These results revealed the crucial role of Senp2-Setdbl axis in controlling adipose lipid storage.
