Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production

 Saitoh T., et al. Nature. 456, 264-268 (2008).

Speaker : Chia-Ming Liu (劉佳明)                                Time: 14:10~15:00, Jun. 03, 2009

Commentator: Dr. Shen-Jeu Won (翁舷誌 博士)        Place: Room 601

Abstract:

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract and is precipitated by the combination of ubiquitous commensal bacteria and hyperactive host mucosal immune responses, although the molecular mechanisms that cause this disease are poorly understood. Recent genome-wide association studies identified autophagy protein Atg16L1 as a candidate gene responsible for susceptibility to Crohn’s disease¹. Autophagy is a lysosomal pathway for degrading various cellular constituents such as long-lived proteins, and plays a role in preventing various diseases². In this paper, the role of Atg16L1 in autophagosome formation as well as its role in inflammation was studied. In Atg16L1 deficient mouse embryonic fibroblasts (MEFs), formation of autophagosomes under the starved condition was not observed and resulting in a decrease of the bulk degradation of long-lived proteins. Although Atg16L1 associates with Atg12-Atg5, Atg16L1 was dispensable for Atg12 conjugation to Atg5. But Atg16L1 was required for LC3 conjugation to PE. However, the Atg16L1-deficient macrophages produced a high amount of interleukin 1β (IL-1β) in response to lipopolysaccharide(LPS), a ligand for Toll-like receptor 4 (TLR4). The Atg16L1 deficiency caused TIR-domain-containing adapter-inducing interferon-β (TRIF) dependent activation of caspase-1 leading to increase production of IL-1β. Mice lacking Atg16L1 in hematopoietic cells were highly susceptible to dextran sulphate sodium (DSS) induced acute colitis that have high level of IL-1β, indicating that the Atg16L1 played an important role in the suppression of intestinal inflammation. This finding suggests that Atg16L1 is an important component in the autophagy formation and is responsible for control of the endotoxin induced inflammatory response.

References:

1.          Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211(2007).

2.          Mizushima, N., et al. Autophagy fights disease through cellular self-digestion. Nature. 451, 1069–1075(2008).