HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway.
The HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the trans-Golgi network (TGN) enables HIV-1 to escape immune surveillance. However, the cellular pathway used by Nef to downregulate MHC-I is unknown. Here, we show that Nef and PACS-1 combine to usurp the ARF6 endocytic pathway by a PI3K-dependent process and downregulate cell surface MHC-I to the TGN. This mechanism requires the hierarchical actions of three Nef motifs-the acidic cluster 62EEEE(65), the SH3 domain binding site 72PXXP(75), and M(20)-in controlling PACS-1-dependent sorting to the TGN, ARF6 activation, and sequestering internalized MHC-I to the TGN, respectively. These data provide new insights into the cellular basis of HIV-1 immunoevasion.
Blagoveshchenskaya
Anastassia D
AD
Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Thomas
Laurel
L
Feliciangeli
Sylvain F
SF
Hung
Chien Hui
CH
Thomas
Gary
G
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D020816:Amino Acid Motifs; D001665:Binding Sites; D001692:Biological Transport; D015704:CD4 Antigens / Q000096:biosynthesis; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D004705:Endocytosis; D005786:Gene Expression Regulation; D015693:Gene Products, nef / Q000378:metabolism / Q000502:physiology*; D005805:Genes, MHC Class I / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013696:Temperature; D013997:Time Factors; D014407:Tumor Cells, Cultured; D033921:Vesicular Transport Proteins; D018909:src Homology Domains; D021601:trans-Golgi Network / Q000378:metabolism
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D015704:CD4 Antigens; D002352:Carrier Proteins; D015693:Gene Products, nef; D019869:Phosphatidylinositol 3-Kinases; D033921:Vesicular Transport Proteins; C491914:PACS1 protein, human; C000715348:ARF6 protein, human