title: C13orf31 (FAMIN) is a central regulator of immunometabolic function.
abstract: 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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: M Zaeem
authors.initials: MZ
authors.lastname: Cader
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Katharina
authors.initials: K
authors.lastname: Boroviak
authors.affiliation: Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Assadi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kempster
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Sewell
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Svetlana
authors.identifier: 0000-0002-0644-9752
authors.initials: S
authors.lastname: Saveljeva
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Ashcroft
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Subhankar
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Centre for Lung Infection, Cambridge, UK.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Brown
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Markus
authors.identifier: 0000-0002-0060-4790
authors.initials: M
authors.lastname: Tschurtschenthaler
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Raine
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Brendan
authors.initials: B
authors.lastname: Doe
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Addenbrooke's and Papworth Hospitals, University of Cambridge, Cambridge, UK.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Jules L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kaneider
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Centre for Lung Infection, Cambridge, UK.|Division of Respiratory Medicine, Department of Medicine, Addenbrooke's and Papworth Hospitals, University of Cambridge, Cambridge, UK.
authors.forename: R Andres
authors.initials: RA
authors.lastname: Floto
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|BioDonostia Health Research Institute San Sebastian and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.affiliation: Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Michael J O
authors.initials: MJ
authors.lastname: Wakelam
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001171:Arthritis, Juvenile / Q000235:genetics*; D001433:Bacteriolysis; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics*; D004734:Energy Metabolism; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007239:Infections / Q000235:genetics*; D058847:Inflammasomes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007918:Leprosy / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012306:Risk; D012772:Shock, Septic / Q000235:genetics*
chemical_list: D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; C000614085:LACC1 protein, human; D011506:Proteins; D000255:Adenosine Triphosphate; D019255:NADPH Oxidases; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I