@article{260475c6eb054c00b2b4871e5c126e1e,
title = "The ubiquitin ligase stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3",
abstract = "Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive Tcells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector Tcell-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 invitro and invivo 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.",
author = "Zuojia Chen and Joseph Barbi and Shurui Bu and Yang, {Huang Yu} and Zhiyuan Li and Yayi Gao and Dilini Jinasena and Juan Fu and Fang Lin and Chen Chen and Jing Zhang and Ning Yu and Xiangpei Li and Zhao Shan and Jia Nie and Zhimei Gao and Hong Tian and Yangyang Li and Zhengju Yao and Ying Zheng and Park, {Benjamin V.} and Ziyi Pan and Jing Zhang and Eric Dang and Zhiguang Li and Honglin Wang and Weibo Luo and Liwu Li and Semenza, {Gregg L.} and Zheng, {Song Guo} and Karin Loser and Andy Tsun and Greene, {Mark I.} and Pardoll, {Drew M.} and Fan Pan and Bin Li",
note = "Funding Information: We thank P. Coffer and J. van Loosdregt for helpful discussions. Our research is supported by National Natural Science Foundation of China grants 30972702, 31170825, 31200647, 31200646, 81271835, 81270083, 31150110337, and 81161120417; National Science and Technology Major Project 2012ZX10002007-003, 2013ZX10003009-002; and the NN-CAS Foundation. B.L. is supported by the Shanghai Science and Technology “Rising Star” Program (10QA1407900) and CAS “100-talent” program. S.Z. is a Tina C. Foundation Lupus Research Award winner. We gratefully acknowledge the support of the SA-SIBS scholarship program and the Knowledge Innovation Program of the Shanghai Institute for Biological Sciences, Chinese Academy of Sciences (2012KIP204). We thank X. Cao and Y.-J. Liu for their critical reading for the manuscript. We thank the members of the Pan and Pardoll Labs for helpful discussions. F.P. is a Stewart Trust Scholar and Melanoma Research Alliance Young Investigator Award winner. F.P.{\textquoteright}s laboratory is partially supported by grants from the National Institutes of Health (RO1AI099300 and RO1AI089830), “Kelly{\textquoteright}s Dream” Foundation, the Janey Fund, and the Seraph Foundation, and gifts from Bill and Betty Topecer and Dorothy Needle. J.B. is supported by a Crohn{\textquoteright}s and Colitis Foundation of America Research Fellowship. ",
year = "2013",
month = aug,
day = "22",
doi = "10.1016/j.immuni.2013.08.006",
language = "English (US)",
volume = "39",
pages = "272--285",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "2",
}