Human immunodeficiency virus type 1 Nef protein targets CD4 to the multivesicular body pathway.
The Nef protein of human immunodeficiency virus type 1 downregulates the CD4 coreceptor from the surface of host cells by accelerating the rate of CD4 endocytosis through a clathrin/AP-2 pathway. Herein, we report that Nef has the additional function of targeting CD4 to the multivesicular body (MVB) pathway for eventual delivery to lysosomes. This targeting involves the endosomal sorting complex required for transport (ESCRT) machinery. Perturbation of this machinery does not prevent removal of CD4 from the cell surface but precludes its lysosomal degradation, indicating that accelerated endocytosis and targeting to the MVB pathway are separate functions of Nef. We also show that both CD4 and Nef are ubiquitinated on lysine residues, but this modification is dispensable for Nef-induced targeting of CD4 to the MVB pathway.
daSilva
Luis L P
LL
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Building 18T, Room 101, National Institutes of Health, Bethesda, MD 20892, USA.
Sougrat
Rachid
R
Burgos
Patricia V
PV
Janvier
Katy
K
Mattera
Rafael
R
Bonifacino
Juan S
JS
D015704:CD4 Antigens / Q000378:metabolism*; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D034622:RNA Interference; D054875:Ubiquitination; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D015704:CD4 Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1