PMID- 29282318 OWN - NLM STAT- MEDLINE DCOM- 20180717 LR - 20200123 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 3 DP - 2018 Jan 16 TI - SRC1 promotes Th17 differentiation by overriding Foxp3 suppression to stimulate RORgammat activity in a PKC-theta-dependent manner. PG - E458-E467 LID - 10.1073/pnas.1717789115 [doi] AB - Th17 cells are major players in multiple autoimmune diseases and are developmentally contingent on reciprocal functionality between the transcription factor Retineic acid receptor-related orphan nuclear receptor gamma (RORgammat) and Forkhead box protein P3 (Foxp3). Here we deciphered a previously unappreciated role of Steroid receptor coactivator 1 (SRC1) in defining the lineage decision for the development of Th17 versus induced T-regulatory (iTreg) cells. We demonstrate that SRC1 functions as a critical coactivator for RORgammat in vivo to promote the functional dominance of RORgammat over Foxp3 and thus establishing an unopposed Th17 differentiation program. In the absence of SRC1, T cell polarization resulted in decreased IL-17(+) and increased Foxp3(+) cells during both in vitro differentiation and in vivo development of experimental autoimmune encephalomyelitis. Mechanistically, T cell receptor (TCR) signaling molecule protein kinase C theta (PKC-theta)-mediated phosphorylation of SRC1 is important for inducing enhanced RORgammat-SRC1 interaction, stable DNA binding, and resultant IL-17A transcription. Furthermore, phospho-SRC1-mediated recruitment of CARM1 induced prominent asymmetric dimethylation of H3R17 while preventing repressive H3K9 trimethylation and hence further modifying the IL-17 locus for optimal transcription. Moreover, binding of phospho-SRC1 to RORgammat displaced bound Foxp3, leading to prompt degradation of the dissociated Foxp3 via a ubiquitin-proteosomal pathway and hence reversing the inhibitory action of Foxp3 on RORgammat activity. Thus, SRC1 acts as a crucial molecular mediator to integrate positive PKC-theta-dependent TCR signals to induce peak RORgammat activity and establish phenotypic dominance of Th17 over the iTreg pathway. FAU - Sen, Subha AU - Sen S AD - Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010. FAU - Wang, Fei AU - Wang F AD - Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010. FAU - Zhang, Jing AU - Zhang J AD - Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010. AD - Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010. FAU - He, Zhiheng AU - He Z AD - Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010. FAU - Ma, Jian AU - Ma J AD - Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010. FAU - Gwack, Yousang AU - Gwack Y AD - Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095. FAU - Xu, Jianming AU - Xu J AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. FAU - Sun, Zuoming AU - Sun Z AUID- ORCID: 0000-0003-1896-6666 AD - Division of 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 PT - Research Support, Non-U.S. Gov't DEP - 20171227 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Forkhead Transcription Factors) RN - 0 (Foxp3 protein, mouse) RN - 0 (Interleukins) 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 - EC 2.7.11.13 (Protein Kinase C-theta) SB - IM MH - Amino Acid Sequence MH - Animals MH - Cell Differentiation/*physiology MH - Forkhead Transcription Factors/genetics/*metabolism MH - Gene Deletion MH - Gene Expression Regulation, Enzymologic/physiology MH - Interleukins/genetics/metabolism MH - Mice MH - Nuclear Receptor Coactivator 1/chemistry/genetics/*metabolism MH - Nuclear Receptor Subfamily 1, Group F, Member 3/genetics/*metabolism MH - Protein Kinase C-theta/genetics/*metabolism MH - Th17 Cells/*physiology PMC - PMC5776998 OTO - NOTNLM OT - EAE OT - T cell differentiation OT - Th17 OT - Treg COIS- The authors declare no conflict of interest. EDAT- 2017/12/29 06:00 MHDA- 2018/07/18 06:00 PMCR- 2018/07/16 CRDT- 2017/12/29 06:00 PHST- 2017/12/29 06:00 [pubmed] PHST- 2018/07/18 06:00 [medline] PHST- 2017/12/29 06:00 [entrez] PHST- 2018/07/16 00:00 [pmc-release] AID - 1717789115 [pii] AID - 201717789 [pii] AID - 10.1073/pnas.1717789115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E458-E467. doi: 10.1073/pnas.1717789115. Epub 2017 Dec 27.