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An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate MHC-I

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      HIV-1 Nef pirates PACS-1 and PACS-2 to downregulate MHC-I, but little is known about the Nef–PACS interaction. The sites on Nef and the PACS proteins required for their interaction are identified, and their importance for Nef trafficking and Nef-induced MHC-I downregulation is discussed. The results provide insight into the molecular basis of Nef action.


      The human immunodeficiency virus type 1 (HIV-1) accessory protein Nef directs virus escape from immune surveillance by subverting host cell intracellular signaling and membrane traffic to down-regulate cell-surface major histocompatibility complex class I (MHC-I). The interaction of Nef with the sorting proteins PACS-1 and PACS-2 mediates key signaling and trafficking steps required for Nef-mediated MHC-I down-regulation. Little is known, however, about the molecular basis underlying the Nef–PACS interaction. Here we identify the sites on Nef and the PACS proteins required for their interaction and describe the consequences of disrupting this interaction for Nef action. A previously unidentified cargo subsite on PACS-1 and PACS-2 interacted with a bipartite site on Nef formed by the EEEE 65 acidic cluster on the N-terminal domain and W 113 in the core domain. Mutation of these sites prevented the interaction between Nef and the PACS proteins on Rab5 (PACS-2 and PACS-1)- or Rab7 (PACS-1)-positive endosomes as determined by bimolecular fluorescence complementation and caused a Nef mutant defective in PACS binding to localize to distorted endosomal compartments. Consequently, disruption of the Nef–PACS interaction repressed Nef-induced MHC-I down-regulation in peripheral blood mononuclear cells. Our results provide insight into the molecular basis of Nef action and suggest new strategies to combat HIV-1.

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            Author and article information

            aVollum Institute, Oregon Health and Science University, Portland, OR 97239
            bDepartment of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239
            University of Geneva
            Author notes

            Present addresses: *Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada

            †Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219.

            1Address correspondence to: Gary Thomas ( thomasg@ or thomasg@ ).
            Role: Monitoring Editor
            Mol Biol Cell
            Mol. Biol. Cell
            Mol. Bio. Cell
            Molecular Biology of the Cell
            The American Society for Cell Biology
            01 June 2012
            : 23
            : 11
            : 2184-2197
            22496420 3364181 E11-11-0928 10.1091/mbc.E11-11-0928
            © 2012 Dikeakos et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (

            “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.

            Membrane Trafficking

            Molecular biology


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