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Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3706-15. doi: 10.1073/pnas.1607592113. Epub 2016 Jun 14.

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.

Author information

1
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.
2
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
3
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
5
Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
6
Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Abstract

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.

KEYWORDS:

N-ethyl-N-nitrosourea; autophagy; cardiomyopathy; cellular metabolism; lymphocyte development

PMID:
27303042
PMCID:
PMC4932993
DOI:
10.1073/pnas.1607592113
[Indexed for MEDLINE]
Free PMC Article

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