Journal Article

C13orf31 (FAMIN) is a central regulator of immunometabolic function

Raine, Tim, Boroviak, Katharina, Kaser, Arthur, Cader, M Zaeem, Assadi, Ghazaleh, Bradley, Allan, Brown, Karen P, Doe, Brendan, Dougan, Gordon, Floto, R Andres, Wakelam, Michael J O, Kempster, Sarah L, Kaneider, Nicole C, Mukhopadhyay, Subhankar, Chilvers, Edwin R, Zhang, Qifeng, Sewell, Gavin W, D'Amato, Mauro, Saveljeva, Svetlana, Clare, Simon, Ashcroft, Jonathan W, Tschurtschenthaler, Markus, Griffin, Jules L

2016

Overview

Variants of the human gene C13orf31 ( LACC1 ) are associated with various disease risks. Kaser and colleagues identify a role for the protein encoded (called ‘FAMIN’) in regulating macrophage fatty-acid oxidation and lipogenesis. Single-nucleotide variations in C13orf31 ( LACC1 ) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/58 / 13/106 / 14/19 / 14/28 / 631/250 / 631/80 / 96/109 / Adenosine Triphosphate - metabolism / Animals / Arthritis, Juvenile - genetics / Autoimmune diseases / Bacteriolysis / Biomedicine / Cells, Cultured / Crohn Disease - genetics / Development and progression / Endotoxins / Energy Metabolism / Fatty Acid Synthase, Type I - metabolism / Fatty acids / Genetic aspects / Genetic Predisposition to Disease / Health aspects / Humans / Immune response regulation / Immunology / Infections - genetics / Infectious Diseases / Inflammasomes - metabolism / Intracellular Signaling Peptides and Proteins / Leprosy - genetics / Lipid Metabolism - genetics / Macrophages - immunology / Mice / Mice, Inbred C57BL / Mice, Knockout / NADPH Oxidases - metabolism / Open reading frames / Oxidation-Reduction / Polymorphism, Single Nucleotide / Properties / Proteins - genetics / Risk / Shock, Septic - genetics / Single nucleotide polymorphisms