Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes

Nat Commun. 2017 Jun 8:8:15614. doi: 10.1038/ncomms15614.

Abstract

Functional consequences for most inflammatory disease-associated loci are incompletely defined, including in the LACC1 (C13orf31) region. Here we show that human peripheral and intestinal myeloid-derived cells express laccase domain-containing 1 (LACC1); LACC1 is expressed in both the cytoplasm and mitochondria. Upon NOD2 stimulation of human macrophages, LACC1 associates with the NOD2-signalling complex, and is critical for optimal NOD2-induced signalling, mitochondrial ROS (mtROS) production, cytokine secretion and bacterial clearance. LACC1 constitutively associates with succinate dehydrogenase (SDH) subunit A, and amplifies pattern recognition receptor (PRR)-induced SDH activity, an important contributor to mtROS production. Relative to LACC1 Ile254, cells transfected with Crohn's disease-risk LACC1 Val254 or LACC1 with mutations of the nearby histidines (249,250) have reduced PRR-induced outcomes. Relative to LACC1 Ile254 carriers, Val254 disease-risk carrier macrophages demonstrate decreased PRR-induced mtROS, signalling, cytokine secretion and bacterial clearance. Therefore, LACC1 is critical for amplifying PRR-induced outcomes, an effect that is attenuated by the LACC1 disease-risk variant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteria / immunology*
  • Cells, Cultured
  • Crohn Disease / genetics
  • Cytokines / metabolism
  • Electron Transport Complex II / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Immunity, Innate / immunology*
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Macrophages / immunology
  • NF-kappa B / metabolism
  • Nod2 Signaling Adaptor Protein / genetics*
  • Proteins / genetics
  • Proteins / immunology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Receptors, Pattern Recognition / immunology*
  • Succinate Dehydrogenase / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • LACC1 protein, human
  • NF-kappa B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, Pattern Recognition
  • Electron Transport Complex II
  • SDHA protein, human
  • Succinate Dehydrogenase
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases