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

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Title: Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity
Authors: Siggs, OM
Stockenhuber, A
Deobagkar-Lele, M
Bull, KR
Crockford, TL
Kingston, BL
Crawford, G
Anzilotti, C
Steeples, V
Ghaffari, S
Czibik, G
Bellahcene, M
Watkins, H
Ashrafian, H
Davies, B
Woods, A
Carling, D
Yavari, A
Beutler, B
Cornall, RJ
Item Type: Journal Article
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.
Issue Date: 28-Jun-2016
Date of Acceptance: 18-Apr-2016
URI: http://hdl.handle.net/10044/1/39189
DOI: https://dx.doi.org/10.1073/pnas.1607592113
ISSN: 1091-6490
Publisher: National Academy of Sciences
Start Page: E3706
End Page: E3715
Journal / Book Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 113
Issue: 26
Copyright Statement: © 2016 Proceedings of the National Academy of Sciences
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
cellular metabolism
lymphocyte development
N-ethyl-N-nitrosourea
cardiomyopathy
autophagy
ACTIVATED PROTEIN-KINASE
PARKINSON-WHITE-SYNDROME
METABOLIC CHECKPOINT
CARDIAC-HYPERTROPHY
LYMPHOCYTE DEVELOPMENT
POLYCYSTIC KIDNEYS
TUMOR-SUPPRESSOR
GENE-EXPRESSION
MOUSE MODEL
AUTOPHAGY
MD Multidisciplinary
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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