Abstract
Mucosal immunity protects a host from intestinal inflammation and infection and is profoundly influenced by symbiotic bacteria. Here we report that in mice symbiotic bacteria directed selective cargo sorting in Paneth cells to promote symbiosis through Nod2, a cytosolic bacterial sensor, and the multifunctional protein kinase LRRK2, both encoded by inflammatory bowel disease (IBD)-associated genes. Commensals recruited Nod2 onto lysozyme-containing dense core vesicles (DCVs), which was required for DCV localization of LRRK2 and a small GTPase, Rab2a. Deficiency of Nod2, LRRK2 or Rab2a or depletion of commensals resulted in lysosomal degradation of lysozyme. Thus, commensal bacteria and host factors orchestrate the lysozyme-sorting process to protect the host from enteric infection, implicating Paneth cell dysfunction in IBD pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Enterocolitis / genetics
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Enterocolitis / immunology*
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Immunity, Mucosal / genetics
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Immunity, Mucosal / immunology*
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Inflammatory Bowel Diseases / genetics
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Inflammatory Bowel Diseases / immunology*
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Intestines / immunology*
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Intestines / microbiology
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Listeriosis / genetics
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Listeriosis / immunology*
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Lysosomes
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Mice
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Mice, Knockout
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Muramidase
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Nod2 Signaling Adaptor Protein / genetics
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Nod2 Signaling Adaptor Protein / immunology
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Paneth Cells / immunology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology*
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Secretory Vesicles / immunology
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Symbiosis / genetics
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Symbiosis / immunology*
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rab GTP-Binding Proteins / genetics
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rab GTP-Binding Proteins / immunology
Substances
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Nod2 Signaling Adaptor Protein
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Nod2 protein, mouse
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Lrrk2 protein, mouse
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Protein Serine-Threonine Kinases
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Muramidase
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Rab2a protein, mouse
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rab GTP-Binding Proteins