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Cited by 30Endoplasmic Reticulum Stress and DiseaseImmune Response and InflammationInflammasome and immune disorders

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LACC1 Required for NOD2-Induced, ER Stress-Mediated Innate Immune Outcomes in Human Macrophages and LACC1 Risk Variants Modulate These Outcomes

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Huang, Chen, Hedl, Matija, Ranjan, Kishu, Abraham, Clara·2019·Cell Reports
DOI 10.1016/j.celrep.2019.11.105PMC PMC7372507
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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.

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  • Endocytotic exodus of microbes in barrier dysfunction Crohn's disease induces mucosal inflammation.

    “Endocytotic exodus of microbes in the barrier dysfunction CD, induces mucosal inflammation [180,181].”

    From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [181]

    The Results section (page unavailable) says impaired microbial clearance in intestinal tissues can increase susceptibility to IBD, and the Introduction (page unavailable) links epithelial-cell defects to intestinal inflammation. Neither passage says that microbes cross a dysfunctional barrier by an endocytotic process or that this process induces mucosal inflammation in Crohn’s disease. (LLM, conf=0.77)

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Metadata

Authors
Huang, C., Hedl, M., Ranjan, K., & Abraham, C.
Affiliations
Yale University (US)
Corresponding author
Abraham, Clara
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-12
Volume
29
Issue
13
Pages
4525-4539.e4
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2019.11.105
PMC
PMC7372507
OpenAlex
W2998191989
Cited by
30
References
3
Citations by year
2025: 7 · 2024: 3 · 2023: 6 · 2022: 3 · 2021: 6 · 2020: 5
FWCI
1.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense (W81XWH-16-1-01-78)
  • National Institutes of Health (R01DK099097, R01DK106593, DKP30-34989, DK062422)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
NOD2, endoplasmic reticulum stress, innate immunity, macrophages, PERK, IRE1α, ATF6, pattern recognition receptors, cytokine production, immune-mediated diseases
MeSH terms
Endoplasmic Reticulum, Endoribonucleases, Escherichia coli, Gene Expression Regulation, HeLa Cells, Humans, Immunity, Innate, Macrophages, Phagocytosis, Risk, Enterococcus faecalis, Signal Transduction, Protein Serine-Threonine Kinases, eIF-2 Kinase, Intracellular Signaling Peptides and Proteins, Activating Transcription Factor 6, Nod2 Signaling Adaptor Protein, Host-Pathogen Interactions, Endoplasmic Reticulum Stress, Primary Cell Culture

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