IL-7 induces rapid clathrin-mediated internalization and JAK3-dependent degradation of IL-7Ralpha in T cells.
Interleukin-7 (IL-7) is an essential cytokine for T-cell development and homeostasis. It is well established that IL-7 promotes the transcriptional down-regulation of IL7RA, leading to decreased IL-7Ralpha surface expression. However, it is currently unknown whether IL-7 regulates the intracellular trafficking and early turnover of its receptor on ligand binding. Here, we show that, in steady-state T cells, IL-7Ralpha is slowly internalized and degraded while a significant fraction recycles back to the surface. On IL-7 stimulation, there is rapid IL-7Ralpha endocytosis via clathrin-coated pits, decreased receptor recycling, and accelerated lysosome and proteasome-dependent degradation. In accordance, the half-life of IL-7Ralpha decreases from 24 hours to approximately 3 hours after IL-7 treatment. Interestingly, we further demonstrate that clathrin-dependent endocytosis is necessary for efficient IL-7 signal transduction. In turn, pretreatment of T cells with JAK3 or pan-JAK inhibitors suggests that IL-7Ralpha degradation depends on the activation of the IL-7 signaling effector JAK3. Overall, our findings indicate that IL-7 triggers rapid IL-7Ralpha endocytosis, which is required for IL-7-mediated signaling and subsequent receptor degradation.
Henriques
Catarina M
CM
Cancer Biology Unit, Instituto de Medicina Molecular, Lisbon University Medical School, Lisbon, Portugal.
Rino
José
J
Nibbs
Robert J
RJ
Graham
Gerry J
GJ
Barata
João T
JT
D002460:Cell Line; D002469:Cell Separation; D022163:Clathrin-Coated Vesicles / Q000276:immunology / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D021381:Protein Transport / Q000502:physiology; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; C507933:JAK3 protein, human; D053616:Janus Kinase 3