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Proc Natl Acad Sci U S A. 2014 May 13;111(19):7066-71. doi: 10.1073/pnas.1406473111. Epub 2014 Apr 30.

Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development.

Author information

  • 1Department of Immunology,Howard Hughes Medical Institute, University of Washington, Seattle, WA 98109; and.
  • 2Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190.
  • 3Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190 mbevan@uw.edu biritani@uw.edu.
  • 4Department of Immunology,Howard Hughes Medical Institute, University of Washington, Seattle, WA 98109; and mbevan@uw.edu biritani@uw.edu.

Abstract

Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1(-/-) mice was arrested at stage 2 (NK1.1(-)CD44(+)) but development of CD4, CD8, γδ T-cell, and NK cell lineages proceeded normally. Enforced expression of a Vα14Jα18 iNKT TCR transgene or loss of the proapoptotic protein Bim did not rescue iNKT cell maturation in Fnip1(-/-) mice. Whereas most known essential transcription factors for iNKT cell development were represented normally, Fnip1(-/-) iNKT cells failed to down-regulate Promyelocytic leukemia zinc finger compared with their WT counterparts. Moreover, Fnip1(-/-) iNKT cells contained hyperactive mTOR and reduced mitochondrial number despite lower ATP levels, resulting in increased sensitivity to apoptosis. These results indicate that Fnip1 is vital for iNKT cell development by maintaining metabolic homeostasis in response to metabolic stress.

KEYWORDS:

Birt-Hogg-Dubé syndrome; metabolism; thymus

PMID:
24785297
[PubMed - indexed for MEDLINE]
PMCID:
PMC4024901
Free PMC Article
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