PMID- 27430721
OWN - NLM
STAT- MEDLINE
DCOM- 20170802
LR  - 20181113
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 197
IP  - 4
DP  - 2016 Aug 15
TI  - Ubiquitination of RORgammat at Lysine 446 Limits Th17 Differentiation by Controlling 
      Coactivator Recruitment.
PG  - 1148-58
LID - 10.4049/jimmunol.1600548 [doi]
AB  - The transcription factor retinoid acid-related orphan receptor gamma t (RORgammat) 
      directs the differentiation of Th17 cells. Th17 cells mediate pathological immune 
      responses responsible for autoimmune diseases, including psoriasis and multiple 
      sclerosis. Previous studies focused on RORgammat target genes and their function in 
      Th17 differentiation. In this study, we assessed posttranscriptional regulation 
      of RORgammat and identified a functional ubiquitination site, K446. Mutation of K446 
      to arginine to prevent ubiquitination greatly enhanced recruitment of steroid 
      receptor coactivator 1 (SRC1), a coactivator critical for RORgammat activity. 
      Correspondingly, the K446 to arginine mutation potentiated Th17 differentiation. 
      We also showed that ubiquitin-specific protease (USP)15 interacted with RORgammat, 
      removed ubiquitin from K446, and stimulated RORgammat activity by enhancing 
      coactivator SRC1 recruitment. Knockdown of USP15 or expression of inactive USP15 
      impaired Th17 differentiation, suggesting a positive role for USP15-mediated 
      deubiquitination of RORgammat in Th17 differentiation. Therefore, ubiquitination of 
      K446 limits RORgammat-mediated Th17 differentiation by inhibiting the recruitment of 
      coactivator SRC1. Our study will inform the development of treatments that target 
      RORgammat ubiquitination pathways to limit Th17-mediated autoimmunity.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - He, Zhiheng
AU  - He Z
AD  - Department of Molecular Immunology, Beckman Research Institute of the City of 
      Hope, Duarte, CA 91010;
FAU - Wang, Fei
AU  - Wang F
AD  - Department of Molecular Immunology, Beckman Research Institute of the City of 
      Hope, Duarte, CA 91010;
FAU - Ma, Jian
AU  - Ma J
AUID- ORCID: 0000-0003-3112-0534
AD  - Department of Molecular Immunology, Beckman Research Institute of the City of 
      Hope, Duarte, CA 91010;
FAU - Sen, Subha
AU  - Sen S
AD  - Department of Molecular Immunology, Beckman Research Institute of the City of 
      Hope, Duarte, CA 91010;
FAU - Zhang, Jing
AU  - Zhang J
AD  - Department of Molecular Immunology, Beckman Research Institute of the City of 
      Hope, Duarte, CA 91010; Irell & Manella Graduate School of Biological Sciences, 
      City of Hope, Duarte, CA 91010;
FAU - Gwack, Yousang
AU  - Gwack Y
AUID- ORCID: 0000-0002-2821-9245
AD  - Department of Physiology, David Geffen School of Medicine, University of 
      California, Los Angeles, Los Angeles, CA 90095; and.
FAU - Zhou, Yu
AU  - Zhou Y
AD  - Research Center for Liver Disease, Keck School of Medicine of University of 
      Southern California, Los Angeles, CA 90089.
FAU - Sun, Zuoming
AU  - Sun Z
AUID- ORCID: 0000-0003-1896-6666
AD  - Department of Molecular Immunology, Beckman Research Institute of the City of 
      Hope, Duarte, CA 91010; zsun@coh.org.
LA  - eng
GR  - R01 AI053147/AI/NIAID NIH HHS/United States
GR  - R01 AI109644/AI/NIAID NIH HHS/United States
GR  - R01 AI083432/AI/NIAID NIH HHS/United States
GR  - P30 CA016042/CA/NCI NIH HHS/United States
GR  - P30 CA033572/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160718
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Nuclear Receptor Subfamily 1, Group F, Member 3)
RN  - 0 (Rorc protein, mouse)
RN  - EC 2.3.1.48 (Ncoa1 protein, mouse)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/immunology
MH  - Flow Cytometry
MH  - Immunoprecipitation
MH  - Lysine/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Nuclear Receptor Coactivator 1/*metabolism
MH  - Nuclear Receptor Subfamily 1, Group F, Member 3/*metabolism
MH  - Polymerase Chain Reaction
MH  - Th17 Cells/cytology/*immunology/metabolism
MH  - Ubiquitination
PMC - PMC4976012
MID - NIHMS796929
EDAT- 2016/07/20 06:00
MHDA- 2017/08/03 06:00
PMCR- 2017/08/15
CRDT- 2016/07/20 06:00
PHST- 2016/03/29 00:00 [received]
PHST- 2016/06/13 00:00 [accepted]
PHST- 2016/07/20 06:00 [entrez]
PHST- 2016/07/20 06:00 [pubmed]
PHST- 2017/08/03 06:00 [medline]
PHST- 2017/08/15 00:00 [pmc-release]
AID - jimmunol.1600548 [pii]
AID - 10.4049/jimmunol.1600548 [doi]
PST - ppublish
SO  - J Immunol. 2016 Aug 15;197(4):1148-58. doi: 10.4049/jimmunol.1600548. Epub 2016 
      Jul 18.