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

Owen Siggs, Alexander Stockenhuber, Mukta Deobagkar-Lele, Katherine Bull, Tanya Crockford, Bethany Kingston, Greg Crawford, Consuelo Anzilotti, Violetta Steeples, Sahar Ghaffari, Gabor Czibik, Mohamed Bellahcene, Hugh Watkins, Houman Ashrafian, Benjamin Davies, Angela Woods, David Carling, Arash Yavan, Bruce Beutler, Richard Cornall

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    19 Citations (Scopus)

    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 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.

    Original languageEnglish
    Pages (from-to)E3706-E3715
    Number of pages10
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume113
    Issue number26
    DOIs
    Publication statusPublished - 2016

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    Siggs, O., Stockenhuber, A., Deobagkar-Lele, M., Bull, K., Crockford, T., Kingston, B., Crawford, G., Anzilotti, C., Steeples, V., Ghaffari, S., Czibik, G., Bellahcene, M., Watkins, H., Ashrafian, H., Davies, B., Woods, A., Carling, D., Yavan, A., Beutler, B., & Cornall, R. (2016). Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity. Proceedings of the National Academy of Sciences of the United States of America, 113(26), E3706-E3715. https://doi.org/10.1073/pnas.1607592113