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

Cell Rep. 2019 Dec 24;29(13):4525-4539.e4. doi: 10.1016/j.celrep.2019.11.105.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / immunology
  • Endoplasmic Reticulum / immunology
  • Endoplasmic Reticulum / microbiology
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / immunology*
  • Endoribonucleases / genetics
  • Endoribonucleases / immunology
  • Enterococcus faecalis / growth & development
  • Enterococcus faecalis / immunology
  • Escherichia coli / growth & development
  • Escherichia coli / immunology
  • Gene Expression Regulation
  • HeLa Cells
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunity, Innate*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / immunology*
  • Phagocytosis
  • Primary Cell Culture
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology
  • Risk
  • Signal Transduction
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / immunology

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Intracellular Signaling Peptides and Proteins
  • LACC1 protein, human
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • EIF2AK3 protein, human
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases