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.

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Acknowledgements

We thank G. Brown for help with laccase assays; J. Murkin and M. Deery for proteomics; L. Porter for metabolic-flux assays; J. Skepper for electron microscopy; I. Purvis for help with in vivo procedures; R. Rodrigues, M. Md-Ibrahim and J. Jones for cellular assays; S. Dhillon for the generation of constructs; T. Lawley, M. Pardo, J. Choudhary, K. Smith, J. Lee, D. Thomas, G. Schneditz, L. Haag, M. Parkes and R. Blumberg for discussions; all National Institute for Health Research Cambridge BioResource volunteers for the participation; the Cambridge BioResource staff for help with volunteer recruitment; members of the Cambridge BioResource SAB and Management Committee for support of this study; and the National Institute for Health Research Cambridge BRC Cell Phenotyping Hub for expertise and help. Access to Cambridge BioResource volunteers and their data and samples is governed by the Cambridge BioResource SAB (documents on access arrangements and contact details, http://www.cambridgebioresource.org.uk/). Supported by the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement 260961 (A.K.), the Wellcome Trust (investigator award 106260/Z/14/Z to A.K.; a PhD fellowship for clinicians to M.Z.C.; and a Career Re-Entry Fellowship to N.C.K.), the Wellcome Trust Sanger Institute (G.D., A.B., S.M., S.C. and K.B.), the US National Institutes of Health (5U420D011174 and 5U54HG006348 to A.B. and K.B.), the Biotechnology and Biological Sciences Research Council (M.J.O.W.), the National Institute for Health Research Cambridge Biomedical Research Centre, the European Crohn's and Colitis Organisation (M.T.) and the Swedish Medical Research Council and the Olle Engkvist foundation (M.D'A.).

Author information

Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

    • M Zaeem Cader
    • , Sarah L Kempster
    • , Gavin W Sewell
    • , Svetlana Saveljeva
    • , Jonathan W Ashcroft
    • , Markus Tschurtschenthaler
    • , Tim Raine
    • , Nicole C Kaneider
    •  & Arthur Kaser
  2. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Katharina Boroviak
    • , Simon Clare
    • , Subhankar Mukhopadhyay
    • , Brendan Doe
    • , Allan Bradley
    •  & Gordon Dougan
  3. Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK.

    • Qifeng Zhang
    •  & Michael J O Wakelam
  4. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

    • Ghazaleh Assadi
    •  & Mauro D'Amato
  5. Cambridge Institute for Medical Research, University of Cambridge, Cambridge Centre for Lung Infection, Cambridge, UK.

    • Karen P Brown
    •  & R Andres Floto
  6. Division of Respiratory Medicine, Department of Medicine, Addenbrooke's and Papworth Hospitals, University of Cambridge, Cambridge, UK.

    • Edwin R Chilvers
    •  & R Andres Floto
  7. Department of Biochemistry, University of Cambridge, Cambridge, UK.

    • Jules L Griffin
  8. BioDonostia Health Research Institute San Sebastian and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.

    • Mauro D'Amato

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Contributions

M.Z.C., together with S.L.K., G.W.S., S.S., J.W.A., M.T., T.R. and N.C.K., designed and performed most of the experiments; K.B., B.D. and A.B. designed, generated and confirmed the genotype of CRISPR-Cas9–generated mouse lines; Q.Z. and M.J.O.W. provided lipidomics experiments and analysis; G.A. and M.D'A. identified the cellular localization of FAMIN; S.C., S.M. and G.D. contributed Salmonella and part of the in vivo experimentation; K.P.B. and R.A.F. contributed to mycobacterial experiments; E.R.C. helped with metabolic-flux assays and ROS experimentation; J.L.G. contributed metabolomics experimentation and analysis; and A.K. devised and coordinated the project and, together with M.Z.C. and G.D., and with contributions from all authors, designed experiments, interpreted data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Arthur Kaser.

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https://doi.org/10.1038/ni.3532

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