The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rα surface expression.
IL-7Rα-mediated signals are essential for naive T lymphocyte survival. Recent studies show that IL-7Rα is internalized and either recycled to cell surface or degraded. However, how the intracellular process of IL-7Rα trafficking is regulated is unclear. In this paper, we show that Vps34, the class III PI3K, plays a critical role in proper IL-7Rα intracellular trafficking. Mice lacking Vps34 in T lymphocytes had a severely reduced T lymphocyte compartment. Vps34-deficient T lymphocytes exhibit increased death and reduced IL-7Rα surface expression, although three major forms of autophagy remain intact. Intracellular IL-7Rα in normal T lymphocytes at steady state is trafficked through either early endosome/multivesicular bodies to the late endosome-Golgi for surface expression or to the lysosome for degradation. However, Vps34-deficient T cells have mislocalized intracellular Eea1, HGF-regulated tyrosine kinase substrate, and Vps36 protein levels, the combined consequence of which is the inability to mobilize internalized IL-7Rα into the retromer pathway for surface display. Our studies reveal that Vps34, though dispensable for autophagy induction, is a critical regulator of naive T cell homeostasis, modulating IL-7Rα trafficking, signaling, and recycling.
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Ian X
IX
McLeod
Xiang
X
Zhou
Qi-Jing
QJ
Li
Fan
F
Wang
You-Wen
YW
He
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics; D001343:Autophagy / Q000235:genetics / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D058546:Class III Phosphatidylinositol 3-Kinases / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D058546:Class III Phosphatidylinositol 3-Kinases