C13orf31 (FAMIN) is a central regulator of immunometabolic function

被引：133

作者：

Cader, M. Zaeem ^{[1
]}

Boroviak, Katharina ^{[2
]}

Zhang, Qifeng ^{[3
]}

Assadi, Ghazaleh ^{[4
]}

Kempster, Sarah L. ^{[1
]}

Sewell, Gavin W. ^{[1
]}

Saveljeva, Svetlana ^{[1
]}

Ashcroft, Jonathan W. ^{[1
]}

Clare, Simon ^{[2
]}

Mukhopadhyay, Subhankar ^{[2
]}

Brown, Karen P. ^{[5
]}

Tschurtschenthaler, Markus ^{[1
]}

Raine, Tim ^{[1
]}

Doe, Brendan ^{[2
]}

Chilvers, Edwin R. ^{[6
,7
]}

Griffin, Jules L. ^{[8
]}

Kaneider, Nicole C. ^{[1
]}

Floto, R. Andres ^{[5
,6
,7
]}

D'Amato, Mauro ^{[4
,9
,10
]}

Bradley, Allan ^{[2
]}

Wakelam, Michael J. O. ^{[3
]}

Dougan, Gordon ^{[2
]}

Kaser, Arthur ^{[1
]}

机构：

[1] Univ Cambridge, Addenbrookes Hosp, Div Gastroenterol & Hepatol, Dept Med, Cambridge, England

[2] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, Cambs, England

[3] Babraham Inst, Signalling Programme, Babraham Res Campus, Cambridge, England

[4] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden

[5] Univ Cambridge, Cambridge Inst Med Res, Cambridge Ctr Lung Infect, Cambridge, England

[6] Univ Cambridge, Addenbrookes Hosp, Div Resp Med, Dept Med, Cambridge, England

[7] Univ Cambridge, Papworth Hosp, Div Resp Med, Dept Med, Cambridge, England

[8] Univ Cambridge, Dept Biochem, Cambridge, England

[9] Basque Fdn Sci, BioDonostia Hlth Res Inst San Sebastian, Bilbao, Spain

[10] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

来源：

NATURE IMMUNOLOGY | 2016年 / 17卷 / 09期

基金：

英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院; 英国生物技术与生命科学研究理事会; 欧洲研究理事会;

关键词：

JUVENILE IDIOPATHIC ARTHRITIS; FATTY-ACID SYNTHASE; BACTERICIDAL ACTIVITY; MITOCHONDRIAL ROS; T-CELLS; METABOLISM; EXPRESSION; OXIDATION; POLARIZATION; PATHOGENESIS;

D O I：

10.1038/ni.3532

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：1046 / 1056

页数：11

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