Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.
Folliculin (FLCN) is a tumor-suppressor protein mutated in the Birt-Hogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive loss-of-function variant of Fnip1 Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells. FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK. Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium, whereas AMPK-dependent unc-51-like autophagy activating kinase 1 (ULK1) phosphorylation and autophagy were increased in FNIP1-deficient B-cell progenitors. These data support a role for FNIP1 as a negative regulator of AMPK.
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom; owen.siggs@gmail.com Bruce.Beutler@UTSouthwestern.edu rcornall@well.ox.ac.uk.
Owen M
OM
Siggs
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Alexander
A
Stockenhuber
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
Mukta
M
Deobagkar-Lele
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
Katherine R
KR
Bull
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
Tanya L
TL
Crockford
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
Bethany L
BL
Kingston
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
Greg
G
Crawford
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
Consuelo
C
Anzilotti
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Violetta
V
Steeples
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Sahar
S
Ghaffari
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Gabor
G
Czibik
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Mohamed
M
Bellahcene
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Hugh
H
Watkins
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Houman
H
Ashrafian
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
Benjamin
B
Davies
Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
Angela
A
Woods
Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
David
D
Carling
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
Arash
A
Yavari
Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Bruce
B
Beutler
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
Richard J
RJ
Cornall
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002452:Cell Count; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C526060:Bhd protein, mouse; D002352:Carrier Proteins; C581709:FNIP1 protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C576788:PRKAG2 protein, mouse; D055372:AMP-Activated Protein Kinases
N-ethyl-N-nitrosourea; autophagy; cardiomyopathy; cellular metabolism; lymphocyte development