Functional analyses of the Crohn's disease risk gene LACC1

Ghazaleh Assadi, Liselotte Vesterlund, Ferdinando Bonfiglio, Luca Mazzurana, Lina Cordeddu, Danika Schepis, Jenny Mjösberg, Sabrina Ruhrmann, Alessia Fabbri, Vladana Vukojevic, Piergiorgio Percipalle, Florian A. Salomons, Jurga Laurencikiene, Leif Törkvist, Jonas Halfvarson, Mauro D'Amato

Research output: Contribution to journalArticle

Abstract

Background: Genetic 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. Methods: We 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. Results: FAMIN 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. Conclusion: FAMIN 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.

Original languageEnglish (US)
Article numbere0168276
JournalPLoS One
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2016

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Crohn disease
Macrophages
Crohn Disease
Peroxisome Proliferator-Activated Receptors
Peroxisomes
macrophages
peroxisomes
Genes
Tissue
Fatty Acids
genes
Cells
cells
Inflammasomes
leprosy
Laccase
beta oxidation
fatty acid metabolism
Juvenile Arthritis
Flow cytometry

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Assadi, G., Vesterlund, L., Bonfiglio, F., Mazzurana, L., Cordeddu, L., Schepis, D., ... D'Amato, M. (2016). Functional analyses of the Crohn's disease risk gene LACC1. PLoS One, 11(12), [e0168276]. https://doi.org/10.1371/journal.pone.0168276

Functional analyses of the Crohn's disease risk gene LACC1. / Assadi, Ghazaleh; Vesterlund, Liselotte; Bonfiglio, Ferdinando; Mazzurana, Luca; Cordeddu, Lina; Schepis, Danika; Mjösberg, Jenny; Ruhrmann, Sabrina; Fabbri, Alessia; Vukojevic, Vladana; Percipalle, Piergiorgio; Salomons, Florian A.; Laurencikiene, Jurga; Törkvist, Leif; Halfvarson, Jonas; D'Amato, Mauro.

In: PLoS One, Vol. 11, No. 12, e0168276, 01.12.2016.

Research output: Contribution to journalArticle

Assadi, G, Vesterlund, L, Bonfiglio, F, Mazzurana, L, Cordeddu, L, Schepis, D, Mjösberg, J, Ruhrmann, S, Fabbri, A, Vukojevic, V, Percipalle, P, Salomons, FA, Laurencikiene, J, Törkvist, L, Halfvarson, J & D'Amato, M 2016, 'Functional analyses of the Crohn's disease risk gene LACC1', PLoS One, vol. 11, no. 12, e0168276. https://doi.org/10.1371/journal.pone.0168276
Assadi G, Vesterlund L, Bonfiglio F, Mazzurana L, Cordeddu L, Schepis D et al. Functional analyses of the Crohn's disease risk gene LACC1. PLoS One. 2016 Dec 1;11(12). e0168276. https://doi.org/10.1371/journal.pone.0168276
Assadi, Ghazaleh ; Vesterlund, Liselotte ; Bonfiglio, Ferdinando ; Mazzurana, Luca ; Cordeddu, Lina ; Schepis, Danika ; Mjösberg, Jenny ; Ruhrmann, Sabrina ; Fabbri, Alessia ; Vukojevic, Vladana ; Percipalle, Piergiorgio ; Salomons, Florian A. ; Laurencikiene, Jurga ; Törkvist, Leif ; Halfvarson, Jonas ; D'Amato, Mauro. / Functional analyses of the Crohn's disease risk gene LACC1. In: PLoS One. 2016 ; Vol. 11, No. 12.
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AU - Vesterlund, Liselotte

AU - Bonfiglio, Ferdinando

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AU - Cordeddu, Lina

AU - Schepis, Danika

AU - Mjösberg, Jenny

AU - Ruhrmann, Sabrina

AU - Fabbri, Alessia

AU - Vukojevic, Vladana

AU - Percipalle, Piergiorgio

AU - Salomons, Florian A.

AU - Laurencikiene, Jurga

AU - Törkvist, Leif

AU - Halfvarson, Jonas

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