Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling

Defective autophagy is linked to diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease (IBD). However, the mechanisms by which autophagy limits inflammation remain poorly understood. Here we found that loss of the autophagy-related gene Atg1611 promoted accumulation of the adaptor TRIF and downstream signaling in macrophages. Multiplex proteomic profiling identified SQSTM1 and TaxlBP1 as selective autophagy-related receptors that mediated the turnover of TRIF. Knockdown of Taxlbpl increased production of the cytokines IFN-beta and IL-1 beta. Mice lacking Atg1611 in myeloid cells succumbed to lipopolysaccharide-mediated sepsis but enhanced their clearance of intestinal Salmonella typhimurium in an interferon receptor-dependent manner. Human macrophages with the Crohn's disease-associated Atg1611 variant T300A exhibited more production of IFN-beta and IL-1 beta. An elevated interferon-response gene signature was observed in patients with IBD who were resistant to treatment with an antibody to the cytokine TNF. These findings identify selective autophagy as a key regulator of signaling via the innate immune system.