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

Nature Cell Biology volume 2, pages 163–167 (2000)Cite this article

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.

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Figure 1: PACS-1 is required for efficient MHC-I downregulation by Nef.
Figure 2: Nef targets MHC-I from the plasma membrane to the trans-Golgi network in a PACS-1-dependent manner.
Figure 3: PACS-1 binds to Nef in an acidic-cluster-dependent manner.
Figure 4: The N-terminal acidic cluster of Nef mediates the TGN targeting of an internalized Nef-containing chimaeric integral-membrane protein.
Figure 5: The TGN targeting of a CD4–Nef chimaera requires PACS-1.

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Acknowledgements

We thank E. Kiyokawa, S. Pfeffer, M. Robinson, G. Nolan and J. Skowronski for providing various reagents and/or for helpful discussions; B. Wehrle-Haller for assistance with imaging; and M. Loche for the artwork. This study was supported by grants from the Gabriella Giorgi-Cavaglieri Foundation and from the Swiss National Science Foundation to D.T., and from the NIH to D.T. and G.T. V.P. was the recipient of an M.D.–Ph.D. scholarship from the Swiss National Science Foundation.

Correspondence and requests for materials should be addressed to D.T. or G.T.

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Authors and Affiliations

  1. Department of Genetics and Microbiology, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland

    Vincent Piguet, Christelle Borel, Aram Mangasarian & Didier Trono

  2. Department of Dermatology, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland

    Vincent Piguet

  3. Vollum Institute, The Oregon Health Sciences University, Portland, 97201, Oregon, USA

    Lei Wan & Gary Thomas

  4. Department of Physiology, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland

    Nicolas Demaurex

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  1. Vincent Piguet
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Correspondence to Gary Thomas or Didier Trono.

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Piguet, V., Wan, L., Borel, C. et al. HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes. Nat Cell Biol 2, 163–167 (2000). https://doi.org/10.1038/35004038

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