Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry

Nature Immunology 11, 55–62 (2010)

Speaker: Peihua Wu (吳佩樺)                                  Time: 13:10-14:00, Mar 24, 2010

Commentator: Dr. Chih-Peng Chang (張志鵬)   Place: Room 601

**Presentation: In English

Abstract:

Autophagy is a physiologically and immunologically controlled intracellular degradation system that is required for the normal turnover of cytoplasmic constituents and defending against several pathogens (1). However, the detectors which induce autophagy in response to intracellular pathogens remain to be identified. Recent studies have revealed that polymorphisms in nucleotide-binding oligomerization domain-containing-2 (NOD2), an intracellular pattern recognition receptor (PRR), as well as two autophagy-related genes, ATG16L1 and immunity-related GTPase family M, are associated with Crohn’s disease, a chronic autoinflammatory disease (2, 3). The Crohn’s disease-associated polymorphisms show a decrease ability for intracellular pathogen clearance and a dysregulation of inflammatory reponses. Therefore, the authors hypothesized that Nod proteins could link between the detection of pathogen and the induction of autophagy for bacterial clearance. They demonstrated that, activation of Nod1 or Nod2 induced formation of autophagosomes both in vitro and in vivo. While infected Nod1-deficient mouse embryonic fibroblasts (MEFs) withShigella flexneri, bacterial number was decreased in colocalization with GFP-LC3 signal whereas coincident with a increase in the survival rate of intracellular bacteria compared to that in wild-type cells. Using immunofluorescene staining and immunoprecipitation analysis, they revealed that Nod proteins were colocalized with ATG16L1 at the plasma membrane and the bacterial entry site. Futhermore, they investigated mutant NOD2, most prevalent polymorphsim in Crohn‘s disease, failed to interact with ATG16L1 at the plasma membrane or the bacterial entry site as well as induce autophagy after S. flexneri infection. These results indicate a link between Nod proteins and ATG16L1 in the bacteria-induced autophagy, suggesting a novel mechanism implicated in the pathogenesis of Crohn’s disease.

Reference

1.          Levine, B. & Deretic, V., Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 7 (10), 767-777 (2007).

2.          Hugot, J.P. et al., Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411 (6837), 599-603 (2001).

3.          Rioux, J.D. et al., Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39 (5), 596-604 (2007).