ENDOCYTOSIS OF THE COMMON CYTOKINE RECEPTOR GAMMA(C) CHAIN - IDENTIFICATION OF SEQUENCES INVOLVED IN INTERNALIZATION AND DEGRADATION

The common cytokine receptor gamma(c), 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 gamma (c) is internalized and degraded in lymphoid cells. To identify gamma( c) regions involved in sorting along the endocytic pathway, we have st udied a chimeric protein composed of the extracellular part of interle ukin 2-receptor alpha and transmembrane and intracellular part of gamm a(c) alpha gamma gamma(wt). When transfected in Jurkat T cells, alpha gamma gamma(wt) is as efficiently internalized and degraded as gamma(c ), demonstrating that the transmembrane and cytosolic tail of gamma(c) carry sequences involved in this process. To identify these motifs, w e have analyzed the trafficking of chimeric proteins with serial trunc ations in their cytosolic tail. Internalization studies showed that th e cytosolic tail of gamma(c) contains three regions located between cy tosolic amino acids 1-35, 35-40, and 40-65 involved in gamma(c) endocy tosis. Successive deletions of these motifs result in reduced endocyto sis. One region containing the 5 cytosolic amino acids 36-40 is essent ial to direct gamma(c) to the degradation pathway. These sorting seque nces, by participating in the fine tuning of cell surface gamma(c) exp ression, might somewhat regulate the cell responsiveness to interleuki ns whose receptors share this component.