HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane.

The Journal of Biological Chemistry
Wing Fai LiThomas E Smithgall

Abstract

The HIV-1 virulence factor Nef promotes high-titer viral replication, immune escape, and pathogenicity. Nef interacts with interleukin-2-inducible T-cell kinase (Itk) and Bruton's tyrosine kinase (Btk), two Tec-family kinases expressed in HIV-1 target cells (CD4 T cells and macrophages, respectively). Using a cell-based bimolecular fluorescence complementation assay, here we demonstrate that Nef recruits both Itk and Btk to the cell membrane and induces constitutive kinase activation in transfected 293T cells. Nef homodimerization-defective mutants retained their interaction with both kinases but failed to induce activation, supporting a role for Nef homodimer formation in the activation mechanism. HIV-1 infection up-regulates endogenous Itk activity in SupT1 T cells and donor-derived peripheral blood mononuclear cells. However, HIV-1 strains expressing Nef variants with mutations in the dimerization interface replicated poorly and were significantly attenuated in Itk activation. We conclude that direct activation of Itk and Btk by Nef at the membrane in HIV-infected cells may override normal immune receptor control of Tec-family kinase activity to enhance the viral life cycle.

References

Jan 26, 1995·The New England Journal of Medicine·F KirchhoffR C Desrosiers
Jul 18, 1997·The Journal of Biological Chemistry·S D BriggsT E Smithgall
Apr 5, 2000·The Journal of Biological Chemistry·A ManninenK Saksela
Aug 25, 2004·Biochemistry·Tai-An LinSteven B Kanner
Jul 20, 2006·The Journal of Biological Chemistry·Ronald P TribleThomas E Smithgall
Apr 7, 2007·Proceedings of the National Academy of Sciences of the United States of America·Massimo PizzatoHeinrich G Göttlinger
Apr 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Julie A ReadingerPamela L Schwartzberg
Sep 24, 2008·Retrovirology·John L Foster, J Victor Garcia
Sep 29, 2009·Journal of Molecular Biology·Jerrod A Poe, Thomas E Smithgall
Jun 4, 2010·Cold Spring Harbor Perspectives in Biology·Amy H AndreottiLeslie J Berg
Apr 12, 2014·The Journal of Biological Chemistry·Sreya TarafdarThomas E Smithgall
Jun 7, 2014·Frontiers in Microbiology·Stéphane Basmaciogullari, Massimo Pizzato
Jan 15, 2015·Biochimica Et Biophysica Acta·Emily N Pawlak, Jimmy D Dikeakos
Sep 30, 2015·Nature·Yoshiko UsamiHeinrich G Göttlinger
Sep 30, 2015·Nature·Annachiara RosaMassimo Pizzato
Feb 8, 2016·Bioorganic & Medicinal Chemistry Letters·Lori A Emert-SedlakThomas E Smithgall
Oct 21, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Robert Roskoski
Nov 1, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Tianjiao WangRyan A Wilcox
Dec 21, 2017·Journal of Molecular Biology·Jamie A MorocoJohn R Engen
Dec 23, 2017·Trends in Biochemical Sciences·Adam H CourtneyArthur Weiss
May 24, 2018·Nature Reviews. Immunology·Guillaume GaudPaul E Love
May 12, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jean K ChungJay T Groves

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Citations

Aug 31, 2020·The Journal of Biological Chemistry·Ryan P StaudtThomas E Smithgall
Sep 3, 2020·The Journal of Biological Chemistry·Ryan P Staudt, Thomas E Smithgall

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