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The Journal of Immunology, 2002, 169: 1959-1969.
Copyright © 2002 by The American Association of Immunologists

Lipid Microdomains Are Required Sites for the Selective Endocytosis and Nuclear Translocation of IFN-{gamma}, Its Receptor Chain IFN-{gamma} Receptor-1, and the Phosphorylation and Nuclear Translocation of STAT1{alpha}1

Prem S. Subramaniam2 and Howard M. Johnson

Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611

IFN-{gamma} contains a nuclear localization sequence that may play a role in the nuclear transport of activated STAT1{alpha} via a complex of IFN-{gamma}/IFN-{gamma} receptor (IFNGR)-1/STAT1{alpha} with the nuclear importer nucleoprotein interactor 1. In this study, we examine the mechanism of endocytosis of IFNGR-1 and the relationship of its nuclear translocation to that of STAT1{alpha}. In untreated WISH cells, both IFNGR-1 and IFNGR-2 were constitutively localized within caveolae-like microdomains isolated from plasma membrane. However, treatment of cells with IFN-{gamma} resulted in rapid migration of IFNGR-1, but not IFNGR-2, from these microdomains. Filipin pretreatment, which specifically inhibits endocytosis from caveolae-like microdomains, inhibited the nuclear translocation of IFN-{gamma} and IFNGR-1 as well as the tyrosine phosphorylation and nuclear translocation of STAT1{alpha}, but did not affect the binding of IFN-{gamma} to these cells. In the Jurkat T lymphocyte cell line, which does not express caveolin-1, nuclear translocation of IFNGR-1 and STAT1{alpha} were similarly inhibited by filipin pretreatment. Isolation of lipid microdomains from Jurkat cells showed that both IFNGR-1 and IFNGR-2 were associated with lipid microdomains only after stimulation with IFN-{gamma}, suggesting that the IFNGR subunits are recruited to lipid microdomains by IFN-{gamma} binding in lymphocytes (Jurkat) in contrast to their constitutive presence in epithelial (WISH) cells. In contrast, treatments that block clathrin-dependent endocytosis did not inhibit either activation or nuclear translocation of STAT1{alpha} or the nuclear translocation of IFN-{gamma} or IFNGR-1. Thus, membrane lipid microdomains play an important role in IFN-{gamma}-initiated endocytic events involving IFNGR-1, and the nuclear translocation of IFN-{gamma}, IFNGR-1, and STAT1{alpha}.




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