HIV-1 Nef promotes endocytosis of cell surface MHC class II molecules via a constitutive pathway.
HIV-1 Nef has been reported to disrupt MHC class II (MHCII)-mediated Ag presentation by a dual strategy that comprises a reduction in cell surface levels of peptide-loaded mature MHCII molecules and a up-regulation of immature MHCII molecules. We show that Nef achieves relocation of MHCII away from the cell surface in monocytic cells by both delaying its transport to the cell surface and by accelerating endocytic removal of cell surface MHCII to a lysosomal compartment. Nef-induced MHCII endocytosis is cholesterol-sensitive but clathrin- and dynamin-independent. Internalized MHCII molecules traverse the early endosomal system and colocalize with pinocytic cargo before reaching lysosomes. Nef-triggered MHCII endocytosis requires Rab5 activity and lyst function, whereas lysosomal trafficking of internalized MHCII molecules requires Rab7 activity. We further show that a similar pathway can remove peptide-MHCII complexes from the surface of monocytic cells not expressing Nef. Our data suggest that Nef uses mechanisms involved in normal MHCII recycling and turnover to mediate the delivery of cell surface MHCII to a lysosomal destination. Thus, Nef-mediated endocytosis of MHCII provides a novel perspective on the regulation of normal MHCII trafficking.
Chaudhry
Ashutosh
A
National Institute of Immunology, New Delhi, India.
Verghese
Divya Anna
DA
Das
Suman Ranjan
SR
Jameel
Shahid
S
George
Anna
A
Bal
Vineeta
V
Mayor
Satyajit
S
Rath
Satyajit
S
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D004705:Endocytosis / Q000235:genetics / Q000276:immunology*; D015693:Gene Products, nef / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006681:HLA-D Antigens / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020298:U937 Cells
D015693:Gene Products, nef; D006681:HLA-D Antigens