Autophagy Restricts Interleukin-1β Signaling via Regulation of P62 Stability

Atg16L1 (autophagy-related 16-like 1), an essential component of autophagy, interacts with the Atg12-Atg5 conjugate for formation of autophagosome. A single nucleotide polymorphism (SNP) in Atg16L1 was identified by genome-wide association studies (GWASs) as a risk factor in Crohn’s disease (CD), along with other autophagy-related genes including LRRK2, NOD2 , and IRGM . These findings suggest that Atg16L1 exerts anti-inflammatory activities in the gastrointestinal (GI) tract. Atg16L1 in macrophages suppresses post-transcriptional maturation of IL-1β in response to TLR4 stimulation, and it regulates the granule exocytosis pathway in Paneth cells specialized in secreting antimicrobial peptides in the GI tract. In addition, it promotes clearance of phagocytosed bacteria in epithelial cells. We investigated how autophagy regulates the innate response to IL-1β. We found that the IL-1β signal transduction pathways are significantly amplified in Atg16L1- or Atg5-deficient mouse embryonic fibroblasts (MEF). Accumulated p62 in autophagy-deficient cells was solely responsible for the amplified IL-1β signaling. We demonstrated that in addition to the autolysosomal degradative pathway, p62 is also degraded by the ubiquitination proteasomal system (UPS). Our genetic and biochemical analyses revealed that Cullin-3 is the E3 ubiquitin ligase of p62, and that Atg16L1 mediates neddylation of Cullin-3, a critical prerequisite for its activation. Taken together, we provided a novel mechanism by which Atg16L1 suppresses a proinflammatory signal.