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

Amit Lahiri, Matija Hedl, Jie Yan and Clara Abraham ()
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Amit Lahiri: Section of Digestive Diseases, Yale University
Matija Hedl: Section of Digestive Diseases, Yale University
Jie Yan: Section of Digestive Diseases, Yale University
Clara Abraham: Section of Digestive Diseases, Yale University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15614

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