The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells  

作　　者：Di Wu Yi Sun 

机构地区：[1]Cancer Institute(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,China [2]Cancer Center of Zhejiang University,Hangzhou 310029,China [3]Zhejang Provincial Clinical Research Center for Cancer,Zhejang Province,China [4]Key Laboratory of Molecular Biology in Medical Sciences,Zhejang Province,China [5]Research Center for Life Science and Human Health,Binjiang Institute of Zhejiang University,Hangzhou 310053,China

出　　处：《Research》2024年第2期373-387,共15页研究（英文）

基　　金：funded by the National Key R&D Program of China(2021YFA1101000 and 2022YFC3401500 to Y.S.);National Natural Science Foundation of China(82172699 and 81801567 to D.W.and U22A20317 and 92253203 to Y.S.);Zhejiang Provincial Natural Science Foundation of China(LY21H100005 to D.W.and LD22H300003 to Y.S.).

摘　　要：Neddylation is necessary for activation of Cullin-RING ligases(CRLs),which degrade various immune regulatory proteins.Our recent study showed that while depletion of neddylation E2-E3 pair Ube2f-Sag in regulatory T(T_(reg))cells had no obvious phenotype,the same depletion of either Ube2m or Rbx1 caused inflammation disorders with different severity.Whether these E2s or E3s compensate each other in functional regulations of T_(reg)cells is,however,previously unknown.In this report,we generated Foxp3^(Cre);Ube2m^(fl/fl);Ube2f^(fl/fl)or Foxp3^(Cre);Rbx1^(fl/fl);Sag^(fl/fl)double-null mice by simultaneous deletion of both neddylation E2s or E3s in T_(reg)cells,respectively.Remarkably,Ube2m&Ube2f double-null mice developed much severe autoimmune phenotypes than did Ube2m-null mice,indicating that Ube2m markedly compensates Ube2f in T_(reg)cells.The minor worsened autoimmune phenotypes seen at the very early stage in Rbx1&Sag double-null than Rbx1-null mice is likely due to already severe phenotypes of the later,indicating a minor compensation of Rbx1 for Sag.The RNA profiling-based analyses revealed that up-and down-regulations of few signaling pathways in T_(reg)cells are associated with the severity of autoimmune phenotypes.Finally,severer inflammation phenotypes seen in mice with double E3-null than with double E2-null T_(reg)cells indicate a neddylation-independent mechanism of 2 E3s,also known to serve as the RING component of CRLs in regulation of T_(reg)cell fitness.

关 键 词：FOXP3 INFLAMMATION markedly 

分 类 号：R730[医药卫生—肿瘤]