| First Author | Zhang S | Year | 2017 |
| Journal | Nature | Volume | 551 |
| Issue | 7678 | Pages | 105-109 |
| PubMed ID | 29072299 | Mgi Jnum | J:283183 |
| Mgi Id | MGI:6098842 | Doi | 10.1038/nature24283 |
| Citation | Zhang S, et al. (2017) Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature 551(7678):105-109 |
| abstractText | T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor beta (TGFbeta) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFbeta enables TH17 cell differentiation remains elusive. Here we reveal that TGFbeta enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor gammat (RORgammat). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFbeta signalling in a RORgammat-dependent manner. Ectopic SMAD4 expression suppresses RORgammat expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFbeta neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFbeta stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFbeta-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORgammat to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFbeta controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases. |
