Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Autophagy / genetics
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Autophagy / immunology
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Bcl-2-Like Protein 11
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Cell Cycle / genetics
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Cell Cycle / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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Class III Phosphatidylinositol 3-Kinases / physiology*
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Gene Expression Regulation / immunology*
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Homeostasis / genetics
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Homeostasis / immunology
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Membrane Proteins / biosynthesis*
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Protein Transport / genetics
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Protein Transport / immunology
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Receptors, Interleukin-7 / biosynthesis*
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Receptors, Interleukin-7 / genetics
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Receptors, Interleukin-7 / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / enzymology*
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / enzymology*
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T-Lymphocytes, Regulatory / immunology*
Substances
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Membrane Proteins
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Proto-Oncogene Proteins
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Receptors, Interleukin-7
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interleukin-7 receptor, alpha chain
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Class III Phosphatidylinositol 3-Kinases