Abstract
Major-histocompatibility-complex (MHC) proteins are used to display, on the surface of a cell, peptides derived from foreign material - such as a virus - that is infecting that cell. Cytotoxic T lymphocytes then recognize and kill the infected cell. The HIV-1 Nef protein downregulates the cell-surface expression of class I MHC proteins, and probably thereby promotes immune evasion by HIV-1. In the presence of Nef, class I MHC molecules are relocalized from the cell surface to the trans-Golgi network (TGN) through as-yet-unknown mechanisms. Here we show that Nef-induced downregulation of MHC-I expression and MHC-I targeting to the TGN require the binding of Nef to PACS-1, a molecule that controls the TGN localization of the cellular protein furin. This interaction is dependent on Nef's cluster of acidic amino acids. A chimaeric integral membrane protein containing Nef as its cytoplasmic domain localizes to the TGN after internalization, in an acidic-cluster- and PACS-1-dependent manner. These results support a model in which Nef relocalizes MHC-I by acting as a connector between MHC-I's cytoplasmic tail and the PACS-1-dependent protein-sorting pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CD4 Antigens / metabolism
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Capsid / antagonists & inhibitors
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Capsid / metabolism*
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Carrier Proteins*
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Cell Line
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Endocytosis / drug effects
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Endocytosis / genetics
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Furin
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Products, nef / metabolism*
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Gene Products, nef / pharmacology
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Golgi Apparatus / metabolism
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HIV-1 / metabolism*
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Histocompatibility Antigens Class I / metabolism*
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Humans
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Hydrogen-Ion Concentration
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Melanoma / metabolism
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Melanoma / pathology
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Membrane Proteins / metabolism
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Oligonucleotides, Antisense / pharmacology
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Protein Structure, Tertiary / genetics
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Rats
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Receptor, IGF Type 2 / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Subtilisins / metabolism
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Transfection
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Vesicular Transport Proteins
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nef Gene Products, Human Immunodeficiency Virus
Substances
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CD4 Antigens
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Carrier Proteins
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Gene Products, nef
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Histocompatibility Antigens Class I
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Membrane Proteins
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Oligonucleotides, Antisense
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PACS1 protein, human
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Pacs1 protein, rat
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Receptor, IGF Type 2
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Recombinant Fusion Proteins
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Vesicular Transport Proteins
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nef Gene Products, Human Immunodeficiency Virus
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Subtilisins
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Furin