Role for lipid rafts in regulating interleukin-2 receptor signaling.
Lipid rafts are plasma membrane microdomains characterized by a unique lipid environment enriched in gangliosides and cholesterol, leading to their insolubility in nonionic detergents. Many receptors are constitutively or inducibly localized in lipid rafts, which have been shown to function as platforms coordinating the induction of signaling pathways. In this report, the first evidence is provided for a role of these lipid microdomains in regulating interleukin-2 receptor (IL-2R) signaling. It is demonstrated that antibody- or ligand-mediated immobilization of components of lipid rafts, glycosyl-phosphatidyl-inositol-anchored proteins, and the GM1 ganglioside, respectively, inhibit IL-2-induced proliferation in T cells. IL-2Ralpha is shown to be constitutively enriched in rafts and further enriched in the presence of immobilized anti-Thy-1. In contrast, IL-2Rbeta and IL-2Rgamma, as well as JAK1 and JAK3, are found in soluble membrane fractions, and their localization is not altered by anti-Thy-1. IL-2-mediated heterotrimerization of IL-2R chains is shown to occur within soluble membrane fractions, exclusively, as is the activation of JAK1 and JAK3. As predicted by these results, the disruption of lipid raft integrity did not impair IL-2-induced signaling. Thus, the sequestration of IL-2Ralpha within lipid microdomains restricts its intermolecular interactions and regulates IL-2R signaling through impeding its association with IL-2Rbeta and IL-2Rgamma.
Marmor
M D
MD
Sunnybrook and Women's College Health Sciences Centre and the Department of Immunology, University of Toronto, Ontario, Canada.
Julius
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D002772:Cholera Toxin / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D004789:Enzyme Activation; D005677:G(M1) Ganglioside / Q000494:pharmacology; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000276:immunology; D047392:beta-Cyclodextrins
D000911:Antibodies, Monoclonal; D003505:Cyclodextrins; D017261:Glycosylphosphatidylinositols; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D018800:Thy-1 Antigens; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D005677:G(M1) Ganglioside; D002772:Cholera Toxin; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3