期刊
IMMUNITY
卷 39, 期 2, 页码 272-285出版社
CELL PRESS
DOI: 10.1016/j.immuni.2013.08.006
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资金
- National Natural Science Foundation of China [30972702, 31170825, 31200647, 31200646, 81271835, 81270083, 31150110337, 81161120417]
- National Science and Technology Major Project [2012ZX10002007-003, 2013ZX10003009-002]
- NN-CAS Foundation
- Shanghai Science and Technology Rising Star Program [10QA1407900]
- CAS 100-talent program
- SA-SIBS scholarship program
- Knowledge Innovation Program of the Shanghai Institute for Biological Sciences, Chinese Academy of Sciences [2012KIP204]
- National Institutes of Health [RO1AI099300, RO1AI089830]
- Kelly's Dream Foundation
- Janey Fund
- Seraph Foundation
- Crohn's and Colitis Foundation of America Research Fellowship
Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer.
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