Editors' ChoiceImmunology

A Nod to Autophagy

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Science Signaling  12 Jan 2010:
Vol. 3, Issue 104, pp. ec14
DOI: 10.1126/scisignal.3104ec14

Autophagy—a process in which cytoplasmic contents are sequestered into autophagosomes before lysosomal degradation—is used as a defense against intracellular bacterial pathogens. Noting that Nod1 and Nod2 detect intracellular bacteria to elicit a proinflammatory response [a process that involves their recruitment of the adaptor RIP2 (receptor interacting protein-2) and the subsequent activation of NF-κB (nuclear factor κB)], Travassos et al. explored the role of these two cytosolic sensors in pathogen-dependent induction of autophagy. Nod1 and Nod2 agonists respectively stimulated autophagy in cultured cells carrying the Nod1 or Nod2 receptor and elicited autophagy in peritoneal macrophages when injected intraperitoneally in mice, responses blunted in mice lacking the respective Nod receptor. Mouse embryo fibroblasts (MEFs) lacking Nod1 showed an impaired autophagic response to Shigella flexneri and Listeria monocytogenes compared with wild-type MEFs (which contain Nod1 but not Nod2), as well as increased bacterial burden. Moreover, inhibitors of autophagy increased bacterial burden in wild-type MEFs but not in those lacking Nod1. The autophagic response to S. flexneri was undiminished in MEFs lacking RIP2 or NEMO (a component of the NF-κB pathway), whereas the NF-κB–dependent secretion of a chemokine in response to bacteria was impaired in MEFs lacking RIP2. A fraction of cellular Nod1 and Nod2 colocalized with the autophagy protein ATG16L1 at the plasma membrane; moreover, tagged Nod1 and Nod2 coimmunoprecipitated with tagged ATG16L1. Nod proteins recruited ATG16L1 to the membrane, even in cells lacking RIP2, and localized with ATG16L1 at bacterial entry sites, whereas a mutant form of Nod2, which is associated with Crohn’s disease and does not localize to the plasma membrane, inhibited ATG16L1 recruitment to invasion sites and bacterial localization to autophagosomes. The authors thus conclude that bacterial autophagy depends on the recruitment of ATG16L1 by Nod proteins independently of RIP2 and the NF-κB pathway.

L. H. Travassos, L. A. M. Carneiro, M. Ramjeet, S. Hussey, Y.-G. Kim, J. G. Magalhães, L. Yuan, F. Soares, E. Chea, L. Le Bourhis, I. G. Boneca, A. Allaoui, N. L. Jones, G. Nuñez, S. E. Girardin, D. J. Philpott, Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55–62 (2010). [PubMed]

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