HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway

Cell. 2002 Dec 13;111(6):853-66. doi: 10.1016/s0092-8674(02)01162-5.

Abstract

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.

Publication types

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

MeSH terms

  • ADP-Ribosylation Factor 6
  • ADP-Ribosylation Factors / metabolism*
  • Amino Acid Motifs
  • Binding Sites
  • Biological Transport
  • CD4 Antigens / biosynthesis
  • Carrier Proteins / metabolism*
  • Cell Line
  • Down-Regulation*
  • Endocytosis*
  • Gene Expression Regulation*
  • Gene Products, nef / metabolism
  • Gene Products, nef / physiology*
  • Genes, MHC Class I / genetics*
  • HeLa Cells
  • Humans
  • Kinetics
  • Microscopy, Fluorescence
  • Models, Biological
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Structure, Tertiary
  • Temperature
  • Time Factors
  • Tumor Cells, Cultured
  • Vesicular Transport Proteins
  • src Homology Domains
  • trans-Golgi Network / metabolism

Substances

  • ADP-Ribosylation Factor 6
  • CD4 Antigens
  • Carrier Proteins
  • Gene Products, nef
  • PACS1 protein, human
  • Vesicular Transport Proteins
  • ADP-Ribosylation Factors
  • ARF6 protein, human