Zbtb44-mediated transcriptional repression critically regulates colonic inflammation.

The regulatory mechanisms that maintain colonic immune homeostasis remain incompletely understood. Here we show that genetic deletion of Zbtb44, a previously uncharacterized member of the ZBTB transcription factor family, leads to spontaneous colitis and rectal prolapse. Zbtb44-/- T cells expressed increased IFN-γ, a pro-inflammatory cytokine strongly associated with human inflammatory bowel disease. Mechanistically, Zbtb44 undergoes SUMOylation, which facilitates its interaction with a conserved SUMO-interacting motif in T-bet, enabling binding to the IFN-γ promoter and enhancer to restrain chronic IFN-γ production. Together, these findings demonstrate that Zbtb44 is a key regulator of colonic inflammation, a role that could be exploited therapeutically.