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

Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3706-15. doi: 10.1073/pnas.1607592113. Epub 2016 Jun 14.


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.

Keywords: N-ethyl-N-nitrosourea; autophagy; cardiomyopathy; cellular metabolism; lymphocyte development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / metabolism
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Count
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Bhd protein, mouse
  • Carrier Proteins
  • FNIP1 protein, mouse
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • PRKAG2 protein, mouse
  • AMP-Activated Protein Kinases