TRIMming TGF-β signals in Th17 cells

Abstract

The precise downstream mediators of TGF-β signaling in Th17 and T reg cells remain unclear. In this issue of JEM, Tanaka et al. report that Trim33 transduces TGF-β signals in Th17 cells to generate an optimal proinflammatory cytokine profile.

Insight from Aaron S. Rapaport and Wenjun Ouyang.

TGF-β signal transduction in iT reg versus Th17 cells. Upon binding of TGF-β to its receptor, the R-Smad components Smad2 and Smad3 are phosphorylated. In iT reg cells, Smad2/3 then associate with Smad4, forming a heterotrimeric complex that mediates canonical TGF-β signaling. Smad2/3/4 translocate to the nucleus and enhance transcription of a regulatory gene signature, notably Foxp3 and Il10. Here, Tanaka et al. (2018) describe a related but contrasting signaling pathway in Th17 cells. Phosphorylated Smad2/3 associates with Trim33, forming a signaling complex that mediates noncanonical TGF-β signaling. Trim33 may also cause the degradation of Smad4 via ubiquitination. Upon translocation to the nucleus, Smad2/3/Trim33 cooperate with RORγt to repress Il10 and amplify Il17a transcription, thereby optimizing Th17 cytokine responses.