1. Academic Validation
  2. Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes

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.
Amit Lahiri 1 Matija Hedl 1 Jie Yan 1 Clara Abraham 1
Affiliations

Affiliation

  • 1 Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut 06510, USA.
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.

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