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

Author

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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)

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.

Suggested Citation

  • Amit Lahiri & Matija Hedl & Jie Yan & Clara Abraham, 2017. "Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15614
    DOI: 10.1038/ncomms15614
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