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 viru s - that is infecting that cell. Cytotoxic T lymphocytes then recognize and kill the infected cell. The HIV-1 Nef protein downregulates the cell-surfa ce 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 reloca lized 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 PAC S-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 d omain localizes to the TGN after internalization, in an acidic-cluster- and PACS-1-dependent manner. These results support a model in which Nef reloca lizes MHC-1 by acting as a connector between MHC-I's cytoplasmic tail and t he PACS-1-dependent protein-sorting pathway.