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A more recent version of this article appeared on January 1, 2004
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Submitted on August 11, 2003
Revised on September 3, 2003
Accepted on September 10, 2003
1 Department of Cell Biology and The Center for Blood Research, Harvard Medical School Boston, U.S.A., These authors contributed equally to this work
2 Department of Cell Biology and The Center for Blood Research, Harvard Medical School Boston, U.S.A.
3 Department of Cell Biology and The Center for Blood Research, Harvard Medical School Boston, U.S.A., Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, U.S.A.
* Corresponding author. E-mail address: kirchhausen{at}crystal.harvard.edu.
HIV Nef has a number of important biological effects, including the down-modulation of several immunological important molecules (CD4, MHC class I). Down-modulation of CD4 appears to be via clathrin-dependent endocytosis, while down-modulation of MHC class I remains unexplained. Several mutant proteins, including mutations in the small GTPase Arf6, have been used to probe membrane traffic pathways. One such mutant has recently been used to propose that Nef acts through Arf6 to activate the endocytosis of MHC class I. Here we show that MHC class I down-modulation is unaffected by other Arf6 mutants that provide more specific perturbations in the GDP-GTP cycling of Arf6. Inhibition of phosphatidylinositol-3-phosphate kinase, an upstream activator of Arf6, also had no effect on the internalization step, but its activity is required to direct MHC class I to the TGN. We conclude that the apparent Arf6 dependency of Nef-mediated MHC class I down-modulation is due to nonspecific perturbations in membrane traffic.
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