Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development.
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.
Department of Immunology,Howard Hughes Medical Institute, University of Washington, Seattle, WA 98109; and.
Heon
H
Park
Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190.
Mark
M
Tsang
Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190 mbevan@uw.edu biritani@uw.edu.
Brian M
BM
Iritani
Department of Immunology,Howard Hughes Medical Institute, University of Washington, Seattle, WA 98109; and mbevan@uw.edu biritani@uw.edu.
Michael J
MJ
Bevan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D058249:Birt-Hogg-Dube Syndrome / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002470:Cell Survival / Q000276:immunology; D004734:Energy Metabolism / Q000276:immunology*; D005260:Female; D006706:Homeostasis / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D002352:Carrier Proteins; C581709:FNIP1 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000255:Adenosine Triphosphate; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
Birt-Hogg-Dubé syndrome; metabolism; thymus