Cutting edge: SIV Nef protein utilizes both leucine- and tyrosine-based protein sorting pathways for down-regulation of CD4.
The Nef protein is unique to primate lentiviruses and is closely linked to accelerated pathogenesis in both human and monkey hosts. Nef acts to down-regulate CD4 and MHC class I, two receptors important for immune function. A recent report demonstrated the presence of two tyrosine motifs in SIV Nef that contribute to its ability to down-regulate CD4 and to associate with clathrin adaptors. These tyrosine motifs are not present in HIV-1 Nef, which instead utilizes a leucine-based motif for its down-regulation of CD4. We now report that SIV Nef also contains a conserved leucine-based motif that contributes to CD4 down-regulation, functions to stimulate internalization, and contributes to the association of SIV Nef with clathrin adaptors AP-1 and AP-2. These results demonstrate that SIV Nef differs from HIV-1 Nef by its ability to use two parallel pathways of the protein-sorting machinery based on either tyrosine or leucine motifs.
Bresnahan
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PA
Gladstone Institute of Virology, Department of Medicine, University of California, San Francisco 94141, USA.
Yonemoto
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W
Greene
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WC
D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007930:Leucine / Q000235:genetics / Q000378:metabolism*; D008251:Macaca; D008565:Membrane Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus
D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D015704:CD4 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D015693:Gene Products, nef; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; D014443:Tyrosine; D007930:Leucine