Travassos, L.H. et al. NOD1 and NOD2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55-62

Department of Immunology, University of Toronto, Toronto, Canada.
Nature Immunology (Impact Factor: 20). 11/2009; 11(1):55-62. DOI: 10.1038/ni.1823
Source: PubMed


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.

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Available from: Leonardo H Travassos
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    • "Another hypothesis that links NOD2 variants to the development of CD involves the recently recognized role of NOD2 in the autophagy pathway. NOD2 interacts with and recruits the CD-associated autophagy protein ATG16L1 to the plasma membrane at bacterial entry sites (Travassos et al., 2010). Furthermore , NOD2 stimulation promotes host cell autophagosome formation, which is associated with an increase in either killing of S. typhimurium or antigen presentation (Cooney et al., 2010; Homer et al., 2010). "
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    ABSTRACT: The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders. Copyright © 2014 Elsevier Inc. All rights reserved.
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    • "NOD1 is an innate immune receptor that recognizes γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), a dipeptide present in peptidoglycan of bacteria, and activates inflammation and autophagy in response to bacterial infection [1], [2]. Loss of NOD1 function increases susceptibility to severe systemic infections and is associated with a variety of inflammatory and autoimmune syndromes in humans [3]–[8]. "
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    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Consequent activation of the key downstream signaling molecules NF-κB and MAP kinase ultimately results in production of inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF-α, and a variety of other cytokines, chemokines and adhesion molecules. The physiological role of NOD2 has been expanding beyond being an innate line of defense against intracellular bacterial infections and equally involves a role in the defense against Toxoplasma[46], as a viral pattern recognition receptor [47], and in the induction of the autophagy process initiated by intracellular bacteria eg Shigella flexneri[48]. "
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    ABSTRACT: Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the triad of granulomatous polyarthritis, dermatitis and uveitis. This paper reviews briefly the classical clinical features of the disease, as well as more recently described extra-triad symptoms. From an ongoing prospective multicenter study, we provide new data on the natural history of Blau syndrome, focusing on functional status and visual outcome. We also present an update of the range of different NOD2 mutations found in Blau syndrome as well as recent data on morphologic and immunohistochemical characteristics of the Blau granuloma. Finally, emerging insights into pathogenic mechanisms including activation of NOD2 signal transduction, and potential biomarkers of disease activity are discussed.
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