Figure 8.

A model for the central role of USP18 in the regulation of type I IFN signaling pathways in pancreatic beta cells. Type I IFNs induce USP18 expression leading to a negative feedback on the STAT signaling pathway. This negative feedback decreases IFNα-induced chemokine production and prevents excessive inflammatory response in pancreatic beta cells. USP18 also inhibits STAT-regulated expression of DP5 and PUMA, and, by an unknown mechanism, expression of Bim. Inhibition of DP5, PUMA and Bim decreases caspases 9/3 activation, reducing IFNα-induced beta cell apoptosis. Interestingly, USP18 inhibits the expression of the T1D candidate gene MDA5, potentially decreasing the proinflammatory response of beta cells to a viral infection