Abstract
LACC1 genetic variants are associated with multiple immune-mediated diseases. However, laccase domain containing-1 (LACC1) functions are incompletely defined. We find that upon stimulation of the pattern-recognition receptor (PRR) NOD2, LACC1 localizes to the endoplasmic reticulum (ER) and forms a complex with ER-stress sensors. All three ER-stress branches, PERK, IRE1α, and ATF6, are required for NOD2-induced signaling, cytokines, and antimicrobial pathways in human macrophages. LACC1, and its localization to the ER, is required for these outcomes. Relative to wild-type (WT) LACC1, transfection of the common Val254 and rare Arg284 immune-mediated disease-risk LACC1 variants into HeLa cells and macrophages, as well as macrophages from LACC1 Val254 carriers, shows reduced NOD2-induced ER stress-associated outcomes; these downstream outcomes are restored by rescuing ER stress. Therefore, we identify ER stress to be essential in PRR-induced outcomes in macrophages, define a critical role for LACC1 in these ER stress-dependent events, and elucidate how LACC1 disease-risk variants mediate these outcomes.
Keywords:
Crohn's disease; ER stress; genetics; inflammatory bowel disease; innate immunity; macrophages; unfolded protein response.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Activating Transcription Factor 6 / genetics
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Activating Transcription Factor 6 / immunology
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Endoplasmic Reticulum / immunology
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Endoplasmic Reticulum / microbiology
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Endoplasmic Reticulum Stress / genetics
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Endoplasmic Reticulum Stress / immunology*
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Endoribonucleases / genetics
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Endoribonucleases / immunology
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Enterococcus faecalis / growth & development
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Enterococcus faecalis / immunology
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Escherichia coli / growth & development
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Escherichia coli / immunology
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Gene Expression Regulation
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HeLa Cells
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Host-Pathogen Interactions / genetics
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Host-Pathogen Interactions / immunology*
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Humans
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Immunity, Innate*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology*
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Macrophages / immunology*
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Macrophages / microbiology
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Nod2 Signaling Adaptor Protein / genetics
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Nod2 Signaling Adaptor Protein / immunology*
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Phagocytosis
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Primary Cell Culture
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Risk
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Signal Transduction
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eIF-2 Kinase / genetics
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eIF-2 Kinase / immunology
Substances
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ATF6 protein, human
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Activating Transcription Factor 6
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Intracellular Signaling Peptides and Proteins
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LACC1 protein, human
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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EIF2AK3 protein, human
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Endoribonucleases