C13orf31 (FAMIN) is a central regulator of immunometabolic function

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

doi:10.1038/ni.3532

C13orf31 (FAMIN) is a central regulator of immunometabolic function

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

124 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1046-1056
Number of pages	11
Journal	Nature Immunology
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/ni.3532
Publication status	Published - 19 Aug 2016
Externally published	Yes

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Publisher Copyright:
© 2016 Nature America, Inc.

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Cader, M. Z., Boroviak, K., Zhang, Q., Assadi, G., Kempster, S. L., Sewell, G. W., Saveljeva, S., Ashcroft, J. W., Clare, S., Mukhopadhyay, S., Brown, K. P., Tschurtschenthaler, M., Raine, T., Doe, B., Chilvers, E. R., Griffin, J. L., Kaneider, N. C., Floto, R. A., D'amato, M., ... Kaser, A. (2016). C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nature Immunology, 17(9), 1046-1056. https://doi.org/10.1038/ni.3532

@article{2ba5d874659445b48d1fb68c4422ee6a,

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = aug,

day = "19",

doi = "10.1038/ni.3532",

language = "English",

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Cader, MZ, Boroviak, K, Zhang, Q, Assadi, G, Kempster, SL, Sewell, GW, Saveljeva, S, Ashcroft, JW, Clare, S, Mukhopadhyay, S, Brown, KP, Tschurtschenthaler, M, Raine, T, Doe, B, Chilvers, ER, Griffin, JL, Kaneider, NC, Floto, RA, D'amato, M, Bradley, A, Wakelam, MJO, Dougan, G & Kaser, A 2016, 'C13orf31 (FAMIN) is a central regulator of immunometabolic function', Nature Immunology, vol. 17, no. 9, pp. 1046-1056. https://doi.org/10.1038/ni.3532

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T1 - C13orf31 (FAMIN) is a central regulator of immunometabolic function

AU - Cader, M. Zaeem

AU - Boroviak, Katharina

AU - Zhang, Qifeng

AU - Assadi, Ghazaleh

AU - Kempster, Sarah L.

AU - Sewell, Gavin W.

AU - Saveljeva, Svetlana

AU - Ashcroft, Jonathan W.

AU - Clare, Simon

AU - Mukhopadhyay, Subhankar

AU - Brown, Karen P.

AU - Tschurtschenthaler, Markus

AU - Raine, Tim

AU - Doe, Brendan

AU - Chilvers, Edwin R.

AU - Griffin, Jules L.

AU - Kaneider, Nicole C.

AU - Floto, R. Andres

AU - D'amato, Mauro

AU - Bradley, Allan

AU - Wakelam, Michael J.O.

AU - Dougan, Gordon

AU - Kaser, Arthur

PY - 2016/8/19

Y1 - 2016/8/19

N2 - 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.

AB - 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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U2 - 10.1038/ni.3532

DO - 10.1038/ni.3532

M3 - Article

C2 - 27478939

AN - SCOPUS:84980390288

SN - 1529-2908

VL - 17

SP - 1046

EP - 1056

JO - Nature Immunology

JF - Nature Immunology

IS - 9

ER -

C13orf31 (FAMIN) is a central regulator of immunometabolic function

Abstract

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