Academic Journal
Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.
| العنوان: | Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity. |
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| المؤلفون: | 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, Yavari, A, Beutler, B, Cornall, R |
| بيانات النشر: | National Academy of Sciences |
| سنة النشر: | 2016 |
| المجموعة: | Oxford University Research Archive (ORA) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://ora.ox.ac.uk/objects/uuid:e398bf8e-18ec-4540-8c5f-e106d78d54cc; https://doi.org/10.1073/pnas.1607592113 |
| DOI: | 10.1073/pnas.1607592113 |
| الاتاحة: | https://doi.org/10.1073/pnas.1607592113 https://ora.ox.ac.uk/objects/uuid:e398bf8e-18ec-4540-8c5f-e106d78d54cc |
| Rights: | info:eu-repo/semantics/embargoedAccess |
| رقم الانضمام: | edsbas.AB348EA4 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1073/pnas.1607592113 |
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