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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.

Original publication

DOI

10.1073/pnas.1607592113

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

14/06/2016

Volume

113

Pages

E3706 - E3715

Addresses

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.

Keywords

B-Lymphocytes, Animals, Mice, Inbred C57BL, Humans, Mice, Cardiomyopathies, Carrier Proteins, Proto-Oncogene Proteins, Tumor Suppressor Proteins, Cell Count, Mutation, AMP-Activated Protein Kinases