首页|The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells
The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells
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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(Treg)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 Treg cells is,however,previously unknown.In this report,we generated Foxp3Cre;Ube2mfl/fl;Ube2ffl/fl or Foxp3Cre;Rbx1fl/fl;Sagfl/fl double-null mice by simultaneous deletion of both neddylation E2s or E3s in Treg 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 Treg cells.The minor worsened autoimmune phenotypes seen at the very early stage in Rbx1&Sag double-null than Rbx1-nu ll 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 Treg 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 Treg cells indicate a neddylation-independent mechanism of 2 E3s,also known to serve as the RING component of CRLs in regulation of Treg cell fitness.
Di Wu、Yi Sun
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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
Cancer Center of Zhejiang University,Hangzhou 310029,China
Zhejiang Provincial Clinical Research Center for Cancer,Zhejiang Province,China
Key Laboratory of Molecular Biology in Medical Sciences,Zhejiang Province,China
Research Center for Life Science and Human Health,B
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National Key R&D Program of ChinaNational Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaZhejiang Provincial Natural Science Foundation of ChinaZhejiang Provincial Natural Science Foundation of China
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