HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes.
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.
Piguet
V
V
Department of Genetics and Microbiology, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland.
Wan
L
L
Borel
C
C
Mangasarian
A
A
Demaurex
N
N
Thomas
G
G
Trono
D
D
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002213:Capsid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D045683:Furin; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D015693:Gene Products, nef / Q000378:metabolism* / Q000494:pharmacology; D006056:Golgi Apparatus / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013381:Subtilisins / Q000378:metabolism; D014162:Transfection; D033921:Vesicular Transport Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D002352:Carrier Proteins; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; C491914:PACS1 protein, human; C113943:Pacs1 protein, rat; D017527:Receptor, IGF Type 2; D011993:Recombinant Fusion Proteins; D033921:Vesicular Transport Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D013381:Subtilisins; D045683:Furin