Endocytosis of the common cytokine receptor gammac chain. Identification of sequences involved in internalization and degradation.
The common cytokine receptor gammac, shared by interleukin 2, 4, 7, 9, and 15 receptors, has a major role in lymphocyte proliferation and differentiation, leading, when mutated, to a genetic disease, X-linked severe combined immunodeficiency. In this study, we report that gammac is internalized and degraded in lymphoid cells. To identify gammac regions involved in sorting along the endocytic pathway, we have studied a chimeric protein composed of the extracellular part of interleukin 2-receptor alpha and transmembrane and intracellular part of gammac, alpha gamma gammawt. When transfected in Jurkat T cells, alpha gamma gammawt is as efficiently internalized and degraded as gammac, demonstrating that the transmembrane and cytosolic tail of gammac carry sequences involved in this process. To identify these motifs, we have analyzed the trafficking of chimeric proteins with serial truncations in their cytosolic tail. Internalization studies showed that the cytosolic tail of gammac contains three regions located between cytosolic amino acids 1-35, 35-40, and 40-65 involved in gammac endocytosis. Successive deletions of these motifs result in reduced endocytosis. One region containing the 5 cytosolic amino acids 36-40 is essential to direct gammac to the degradation pathway. These sorting sequences, by participating in the fine tuning of cell surface gammac expression, might somewhat regulate the cell responsiveness to interleukins whose receptors share this component.
Morelon
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Unité de Biologie des Interactions Cellulaires, URA CNRS 1960, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
Dautry-Varsat
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D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D006207:Half-Life; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
D010446:Peptide Fragments; D018121:Receptors, Cytokine