| First Author | Sen S | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 3 | Pages | E458-E467 |
| PubMed ID | 29282318 | Mgi Jnum | J:260600 |
| Mgi Id | MGI:6113160 | Doi | 10.1073/pnas.1717789115 |
| Citation | Sen S, et al. (2018) SRC1 promotes Th17 differentiation by overriding Foxp3 suppression to stimulate RORgammat activity in a PKC-theta-dependent manner. Proc Natl Acad Sci U S A 115(3):E458-E467 |
| abstractText | 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. |
