HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes

Nat Cell Biol. 2000 Mar;2(3):163-7. doi: 10.1038/35004038.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD4 Antigens / metabolism
  • Capsid / antagonists & inhibitors
  • Capsid / metabolism*
  • Carrier Proteins*
  • Cell Line
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Endocytosis / drug effects
  • Endocytosis / genetics
  • Furin
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Products, nef / metabolism*
  • Gene Products, nef / pharmacology
  • Golgi Apparatus / metabolism
  • HIV-1 / metabolism*
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Melanoma / metabolism
  • Melanoma / pathology
  • Membrane Proteins / metabolism
  • Oligonucleotides, Antisense / pharmacology
  • Protein Structure, Tertiary / genetics
  • Rats
  • Receptor, IGF Type 2 / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Subtilisins / metabolism
  • Transfection
  • Vesicular Transport Proteins
  • nef Gene Products, Human Immunodeficiency Virus


  • CD4 Antigens
  • Carrier Proteins
  • Gene Products, nef
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • Oligonucleotides, Antisense
  • PACS1 protein, human
  • Pacs1 protein, rat
  • Receptor, IGF Type 2
  • Recombinant Fusion Proteins
  • Vesicular Transport Proteins
  • nef Gene Products, Human Immunodeficiency Virus
  • Subtilisins
  • Furin