FAM177A1 Inhibits IL-1β–Induced Signaling by Impairing TRAF6–Ubc13 Association

Abstract The proinflammatory cytokine IL-1β is a crucial mediator of inflammatory responses. IL-1β–induced signaling is finely regulated by various mechanisms, and its imbalance is involved in a variety of diseases. In this study, we identified FAM177A1, a protein of unknown function, as a negative regulator of IL-1β–induced signaling in human cells. Overexpression of FAM177A1 inhibited IL-1β–triggered activation of NF-κB and transcription of inflammatory genes, whereas knockdown of FAM177A1 showed the opposite effects. Mechanistically, FAM177A1 competitively bound to the E3 ubiquitin ligase TRAF6 and impaired its interaction with the E2-conjugating enzyme Ubc13; therefore, it inhibited TRAF6-mediated polyubiquitination and recruitment of downstream signaling molecules. These findings reveal a function of FAM177A1 and promote our understanding of the regulatory mechanisms of IL-1β–induced inflammatory responses.