Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity
Open Access
- 14 June 2016
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (26), 201607592-E3715
- https://doi.org/10.1073/pnas.1607592113
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
Funding Information
- Bill and Melinda Gates Foundation (N/A)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (HHSN272200700038C)
- Wellcome Trust (100083/Z/12/Z)
- Medical Research Council (N/A)
- DH | National Institute for Health Research (N/A)
- British Heart Foundation (N/A)
- British Heart Foundation (N/A)
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