HIV-1 Nef disrupts antigen presentation early in the secretory pathway.
Human immunodeficiency virus, type 1 Nef disrupts viral antigen presentation and promotes viral immune evasion from cytotoxic T lymphocytes. There is evidence that Nef acts early in the secretory pathway to redirect major histocompatibility complex class I (MHC-I) from the trans-Golgi network to the endolysosomal pathway. However, a competing model suggests that Nef acts much later by accelerating MHC-I turnover at the cell surface. Here we demonstrate that Nef targets early forms of MHC-I molecules in the endoplasmic reticulum by preferentially binding hypophosphorylated cytoplasmic tails. The Nef-MHC-I complex migrates normally into the Golgi apparatus but subsequently fails to arrive at the cell surface and become phosphorylated. Cell type-specific differences in the rate of MHC-I transport through the secretory pathway correlate with responsiveness to Nef and co-precipitation of adaptor protein 1 with the Nef.MHC-I complex. We propose that the assembly of a Nef.MHC-I.adaptor protein 1 complex early in the secretory pathway is important for Nef activity.
Kasper
Matthew R
MR
Department of Microbiology, The University of Michigan, Ann Arbor, Michigan 48109, USA.
Roeth
Jeremiah F
JF
Williams
Maya
M
Filzen
Tracey M
TM
Fleis
Rebekah I
RI
Collins
Kathleen L
KL
D000256:Adenoviridae / Q000378:metabolism; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D015693:Gene Products, nef / Q000737:chemistry / Q000502:physiology*; D005805:Genes, MHC Class I; D006056:Golgi Apparatus / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D010710:Phosphates / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D021601:trans-Golgi Network
D015693:Gene Products, nef; D015789:HLA-A2 Antigen; D010710:Phosphates