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

• DOI: 10.1038/ni.1823
• Publication Date: 2009-11-08T18:34:57Z
• Authors: Leonardo H Travassos; Leticia A M Carneiro; Mahendrasingh Ram...; Seamus Hussey; Yun-Gi Kim; João G Magalhães; Linda Yuan; Fraser Soares; Evelyn Chea; Lionel Le Bourhis; Ivo G Boneca; Abdelmounaaim All...; Nicola L Jones; Gabriel Nuñez; Stephen E Girardin; Dana J Philpott
• Keywords: Male; 0301 basic medicine; Cells; Knockout; Green Fluorescent Proteins; Immunoblotting; Inbred Strains; Cell Membrane -- microbiology; Autophagy-Related Proteins; Carrier Proteins -- metabolism; Mice, Inbred Strains; Inbred C57BL; Transfection; Cell Membrane -- metabolism; Electron; Fluorescence; Cell Line; Mice; 03 medical and health sciences; Nod2 Signaling Adaptor Protein -- genetics; Autophagy; Green Fluorescent Proteins -- genetics; Animals; Humans; Green Fluorescent Proteins -- metabolism; Nod1 Signaling Adaptor Protein -- metabolism; Cells, Cultured; Cell Membrane -- ultrastructure; Mice, Knockout; Microscopy; Cultured; Microscopy, Confocal; Bacteria; Cell Membrane; Sciences bio-médicales et agricoles; Nod1 Signaling Adaptor Protein -- genetics; Mice, Inbred C57BL; Microscopy, Electron; Hela Cells; Confocal; Mutation; Carrier Proteins -- genetics; Bacteria -- metabolism; Female; Carrier Proteins; Nod2 Signaling Adaptor Protein -- metabolism; HeLa Cells

Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. In cells homozygous for the Crohn's disease-associated NOD2 frameshift mutation, mutant Nod2 failed to recruit ATG16L1 to the plasma membrane and wrapping of invading bacteria by autophagosomes was impaired. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.