Loading…

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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-06, Vol.113 (26), p.E3706-E3715
Main Authors: Siggs, Owen M., Stockenhuber, Alexander, Deobagkar-Lele, Mukta, Bull, Katherine R., Crockford, Tanya L., Kingston, Bethany L., Crawford, Greg, Anzilotti, Consuelo, Steeples, Violetta, Ghaffari, Sahar, Czibik, Gabor, Bellahcene, Mohamed, Watkins, Hugh, Ashrafian, Houman, Davies, Benjamin, Woods, Angela, Carling, David, Yavari, Arash, Beutler, Bruce, Cornall, Richard J.
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1607592113