Zbtb44-mediated transcriptional repression critically regulates colonic inflammation

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 exhibit elevated expression of IFN-γ, a pro-inflammatory cytokine strongly associated with human inflammatory bowel disease (IBD).

Mechanistically, Zbtb44 undergoes SUMOylation, which facilitates its interaction with a conserved SUMO-interacting motif (SIM) in T-bet, enabling binding to the IFN-γ promoter and enhancer to restrain chronic IFN-γ production. Together, these findings demonstrate Zbtb44 as a key regulator of colonic immune homeostasis and highlight this pathway as a potential therapeutic target in IBD.