10.17863/CAM.1210
Cader, Mohammed
0000-0002-4121-748X
Boroviak, Katharina
Zhang, Qifeng
Assadi, Ghazaleh
Kempster, Sarah L
Sewell, Gavin William
Saveljeva, Svetlana
Ashcroft, Jonathan W
Clare, Simon
Mukhopadhyay, Subhankar
Brown, Karen P
Tschurtschenthaler, Markus
Raine, Tim
Doe, Brendan
Chilvers, Edwin
0000-0002-4230-9677
Griffin, Julian
0000-0003-1336-7744
Kaneider, Nicole C
Floto, Andres
0000-0002-2188-5659
D’Amato, Mauro
Bradley, Allan
0000-0002-2349-8839
Wakelam, Michael
0000-0003-4059-9276
Dougan, Gordon
0000-0003-0022-965X
Kaser, Arthur
C13orf31 (FAMIN) is a central regulator of immunometabolic function
Apollo - University of Cambridge Repository (staging)
2016
cell biology
immunology
Apollo - University of Cambridge Repository (staging)
Apollo - University of Cambridge Repository (staging)
2016-08-15
2016-08-15
2016-08-01
en
Article
1529-2908
https://www.repository.cam.ac.uk/handle/1810/257280
1529-2916
10.1038/ni.3532
Single-nucleotide variations in $\small \textit{C13orf31 (LACC1)}$ 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.
Supported by the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement 260961, the Wellcome Trust (investigator award 106260/Z/14/Z; a PhD fellowship for clinicians; and a Career Re-Entry Fellowship), the Wellcome Trust Sanger Institute, the US National Institutes of Health (5U420D011174 and 5U54HG006348), the Biotechnology and Biological Sciences Research Council, the National Institute for Health Research Cambridge Biomedical Research Centre, the European Crohn’s and Colitis Organisation and the Swedish Medical Research Council and the Olle Engkvist foundation.
This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ni.3532
MRC
MR/P011705/1
Wellcome Trust
103077/Z/13/Z
WELLCOME TRUST
106260/Z/14/Z
European Research Council
260961
Wellcome Trust
100891/Z/13/Z
Wellcome Trust
100675/Z/12/Z