TY - JOUR
T1 - Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity
AU - Siggs, Owen M.
AU - Stockenhuber, Alexander
AU - Deobagkar-Lele, Mukta
AU - Bull, Katherine R.
AU - Crockford, Tanya L.
AU - Kingston, Bethany L.
AU - Crawford, Greg
AU - Anzilotti, Consuelo
AU - Steeples, Violetta
AU - Ghaffari, Sahar
AU - Czibik, Gabor
AU - Bellahcene, Mohamed
AU - Watkins, Hugh
AU - Ashrafian, Houman
AU - Davies, Benjamin
AU - Woods, Angela
AU - Carling, David
AU - Yavari, Arash
AU - Beutler, Bruce
AU - Cornall, Richard J.
N1 - Funding Information:
We thank Xin Lu and Chris Goodnow for mouse strains, Katharina Brandl for help with mapping, Anne Murray for editorial assistance, and Mercedes Gutierrez and Robert Green for animal care. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics, funded by Wellcome Trust Grant 090532/Z/09/Z and MRC Hub Grant G0900747 91070, for the generation of sequencing data. This work was supported by the Bill and Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases, National Institutes of Health Grant HHSN272200700038C (to B.B.), Wellcome Trust Grant 100083/Z/ 12/Z (to O.M.S.), the Medical Research Council (R.J.C.), the UK National Institute for Health Research (A.Y.), and the BHF Centre of Research Excellence, Oxford (H.W. and H.A.).
PY - 2016/6/28
Y1 - 2016/6/28
N2 - 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 lossof-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 ã2 subunit of AMPK. Concordantly, ã2-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.
AB - 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 lossof-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 ã2 subunit of AMPK. Concordantly, ã2-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.
KW - Autophagy
KW - Cardiomyopathy
KW - Cellular metabolism
KW - Lymphocyte development
KW - N-ethyl-N nitrosourea
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U2 - 10.1073/pnas.1607592113
DO - 10.1073/pnas.1607592113
M3 - Article
C2 - 27303042
AN - SCOPUS:84976548266
SN - 0027-8424
VL - 113
SP - E3706-E3715
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -