Abstract
BackgroundGenetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn’s disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression.MethodsWe implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function.ResultsFAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems.ConclusionFAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.
Highlights
The two major forms of inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of unknown etiology, affecting around 2.5 million of Europeans with an incidence that is increasing worldwide [1]
fatty acid metabolism-immune nexus (FAMIN) expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and PLOS ONE | DOI:10.1371/journal.pone
Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems
Summary
The two major forms of inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of unknown etiology, affecting around 2.5 million of Europeans with an incidence that is increasing worldwide [1]. Despite the gained knowledge and advances in IBD genetics, the translation of research findings into functional insight and clinical applications has been difficult, primarily hampered by the fact that many causative genes and their respective pathophysiological roles are still to be elucidated. LACC1 SNPs represent strong genetic risk factors for CD and for leprosy [4,5,6,7,8,9,10], and we have recently reported the occurrence of LACC1 common risk variants in UC and juvenile idiopathic arthritis (JIA) patients [11] This is in addition to previous studies reporting a rare LACC1 missense mutation (Cys284Arg) in monogenic forms of early-onset CD (EOCD) and systemic JIA (sJIA) [12,13]. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression
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