HIV-1 Nef Interacts with Inositol Trisphosphate Receptor to Activate Calcium Signaling in T Cells

HIV-1 pathogenicity factor Nef has been shown to modulate calcium signaling in host cells, but the underlying molecular mechanisms have remained unclear. Here we show that calcium/calcineurin-dependent activation of nuclear factor of activated T cells (NFAT) by Nef in Jurkat T cells requires the endoplasmic reticulum-resident inositol trisphosphate receptor (IP3R), but yet does not involve increase in phospholipase-Cγ1 (PLCγ1)-catalyzed production of IP3 or depletion of IP3-regulated intracellular calcium stores. Nef could be coprecipitated with endogenous IP3R type-1 (IP3R1) from Nef-transfected Jurkat T cells as well as from HIV-infected primary human peripheral mononuclear cells. Thus, the Nef/IP3R1-interaction defines a novel T cell receptor–independent mechanism by which Nef can promote T cell activation, and appears to involve atypical IP3R-triggered activation of plasma membrane calcium influx channels in a manner that is uncoupled from depletion of intracellular calcium stores.

[1]  Richard S Lewis,et al.  Calcium signaling mechanisms in T lymphocytes. , 2001, Annual review of immunology.

[2]  A. McMichael,et al.  Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. , 2001, Immunity.

[3]  A. Capron,et al.  Role of HIV-1 Nef expression in activation pathways in CD4+ T cells. , 1994, AIDS research and human retroviruses.

[4]  J. Cleveland,et al.  Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. , 2000, Immunity.

[5]  K. Saksela,et al.  Synergistic Activation of NFAT by HIV-1 Nef and the Ras/MAPK Pathway* , 2000, The Journal of Biological Chemistry.

[6]  M. Greenberg,et al.  HIV and SIV Nef modulate signal transduction and protein sorting in T cells. , 1999, Cold Spring Harbor symposia on quantitative biology.

[7]  S. Rhee,et al.  Regulation of Phosphoinositide-specific Phospholipase C Isozymes* , 1997, The Journal of Biological Chemistry.

[8]  R. Hurst,et al.  trp, a Novel Mammalian Gene Family Essential for Agonist-Activated Capacitative Ca2+ Entry , 1996, Cell.

[9]  M. Hediger,et al.  Molecular Cloning and Characterization of a Channel-like Transporter Mediating Intestinal Calcium Absorption* , 1999, The Journal of Biological Chemistry.

[10]  D. Trono,et al.  The Nef protein of HIV-1 associates with rafts and primes T cells for activation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Crabtree.  Generic Signals and Specific Outcomes Signaling through Ca2+, Calcineurin, and NF-AT , 1999, Cell.

[12]  J. Putney.  "Kissin' cousins": intimate plasma membrane-ER interactions underlie capacitative calcium entry. , 1999, Cell.

[13]  D. Trono,et al.  The Nef protein of primate lentiviruses , 1999, Reviews in Medical Virology.

[14]  D. Baltimore,et al.  Proline‐rich (PxxP) motifs in HIV‐1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down‐regulation of CD4. , 1995, The EMBO journal.

[15]  K. Mikoshiba,et al.  2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. , 1997, Journal of biochemistry.

[16]  R. Abraham,et al.  Pleiotropic Contributions of Phospholipase C-γ1 (PLC-γ1) to T-Cell Antigen Receptor-Mediated Signaling: Reconstitution Studies of a PLC-γ1-Deficient Jurkat T-Cell Line , 2000, Molecular and Cellular Biology.

[17]  P. Negulescu,et al.  Intracellular calcium dependence of gene expression in single T lymphocytes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Berridge,et al.  Capacitative calcium entry. , 1995, The Biochemical journal.

[19]  Roger J. Davis,et al.  Requirement for Transcription Factor NFAT in Interleukin-2 Expression , 1999, Molecular and Cellular Biology.

[20]  S. Muallem,et al.  Functional interaction between InsP3 receptors and store-operated Htrp3 channels , 1998, Nature.

[21]  M. Vihinen,et al.  SH3-Domain binding function of HIV-1 Nef is required for association with a PAK-related kinase. , 1998, Virology.

[22]  G. Crabtree,et al.  Characterization of the nuclear and cytoplasmic components of the lymphoid-specific nuclear factor of activated T cells (NF-AT) complex. , 1993, The Journal of biological chemistry.

[23]  G. Nabel,et al.  An inducible transcription factor activates expression of human immunodeficiency virus in T cells , 1987, Nature.

[24]  D. Armstrong,et al.  Stable Activation of Single Ca2+ Release-activated Ca2+ Channels in Divalent Cation-free Solutions* , 2001, The Journal of Biological Chemistry.

[25]  P. Hogan,et al.  Transcription factors of the NFAT family: regulation and function. , 1997, Annual review of immunology.

[26]  Keli Xu,et al.  Calcium oscillations increase the efficiency and specificity of gene expression , 1998, Nature.

[27]  J. Putney.  Intimate Plasma Membrane–ER Interactions Underlie Capacitative Calcium Entry: “Kissin' Cousins” , 1999, Cell.

[28]  D. Olive,et al.  Physical and Functional Interaction of Nef with Lck , 1996, The Journal of Biological Chemistry.

[29]  J. Wang,et al.  Identification of intracellular calcium pools. Selective modification by thapsigargin. , 1991, The Journal of biological chemistry.

[30]  A. Marks,et al.  Regulation of the Inositol 1,4,5-Trisphosphate Receptor by Tyrosine Phosphorylation , 1996, Science.

[31]  K. Saksela,et al.  Activation of NFAT-Dependent Gene Expression by Nef: Conservation among Divergent Nef Alleles, Dependence on SH3 Binding and Membrane Association, and Cooperation with Protein Kinase C-θ , 2001, Journal of Virology.

[32]  J. Skowroński,et al.  Separable functions of Nef disrupt two aspects of T cell receptor machinery: CD4 expression and CD3 signaling , 1997, The EMBO journal.

[33]  C. Cheng‐Mayer,et al.  HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. , 1994, Immunity.

[34]  K. Saksela,et al.  Interactions of HIV-1 NEF with cellular signal transducing proteins. , 2000, Frontiers in bioscience : a journal and virtual library.

[35]  T. McDonald,et al.  Inhibition by SK&F 96365 of Ca2+ current, IL‐2 production and activation in T lymphocytes , 1994, British journal of pharmacology.

[36]  G L MADDOX,et al.  A critical evaluation , 2012 .

[37]  L. Ratner,et al.  Human immunodeficiency virus type 1 Nef protein down-regulates transcription factors NF-kappa B and AP-1 in human T cells in vitro after T-cell receptor stimulation , 1994, Journal of virology.

[38]  M. Stevenson,et al.  HIV‐1 replication is controlled at the level of T cell activation and proviral integration. , 1990, The EMBO journal.

[39]  G. Crabtree,et al.  Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression , 1996, Nature.

[40]  M. Feinberg,et al.  Human immunodeficiency virus type 1 Nef does not alter T-cell sensitivity to antigen-specific stimulation , 1997, Journal of virology.

[41]  T. Kurosaki,et al.  Genetic evidence for involvement of type 1, type 2 and type 3 inositol 1,4,5‐trisphosphate receptors in signal transduction through the B‐cell antigen receptor , 1997, The EMBO journal.

[42]  A. Porcelli,et al.  HIV-1 nef expression inhibits the activity of a Ca2+-dependent K+ channel involved in the control of the resting potential in CEM lymphocytes. , 1999, Journal of immunology.

[43]  O. Danos,et al.  Activation pathways and human immunodeficiency virus type 1 replication are not altered in CD4+ T cells expressing the nef protein. , 1992, AIDS research and human retroviruses.

[44]  H. Kung,et al.  Phospholipase C-gamma 1 can induce DNA synthesis by a mechanism independent of its lipase activity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Marsh,et al.  HIV-1 Nef increases T cell activation in a stimulus-dependent manner. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Christopher C. Goodnow,et al.  Differential activation of transcription factors induced by Ca2+ response amplitude and duration , 1997, Nature.

[47]  K. Krause,et al.  The HIV Nef Protein Alters Ca2+ Signaling in Myelomonocytic Cells through SH3-mediated Protein-Protein Interactions* , 1999, The Journal of Biological Chemistry.

[48]  K. Mikoshiba,et al.  Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[49]  J. Putney,et al.  Role of the Phospholipase C-Inositol 1,4,5-Trisphosphate Pathway in Calcium Release-activated Calcium Current and Capacitative Calcium Entry* , 2001, The Journal of Biological Chemistry.

[50]  Roger Y. Tsien,et al.  Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression , 1998, Nature.

[51]  R Marsault,et al.  Transfected Aequorin in the Measurement of Cytosolic Ca2+ Concentration ([Ca2+]c) , 1995, The Journal of Biological Chemistry.

[52]  D. Clapham,et al.  CaT1 manifests the pore properties of the calcium-release-activated calcium channel , 2001, Nature.

[53]  K. Mikoshiba,et al.  Requirement of the inositol trisphosphate receptor for activation of store-operated Ca2+ channels. , 2000, Science.

[54]  T. Swigut,et al.  Mechanism for down‐regulation of CD28 by Nef , 2001, The EMBO journal.

[55]  A. Marks,et al.  The inositol 1,4,5-trisphosphate receptor is essential for T-cell receptor signaling. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[56]  J. Skowroński,et al.  Altered T cell activation and development in transgenic mice expressing the HIV‐1 nef gene. , 1993, The EMBO journal.

[57]  K. Mikoshiba,et al.  Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  A. Guimond,et al.  Nef Harbors a Major Determinant of Pathogenicity for an AIDS-like Disease Induced by HIV-1 in Transgenic Mice , 1998, Cell.

[59]  T. Reinhart,et al.  Association of simian immunodeficiency virus Nef with the T-cell receptor (TCR) zeta chain leads to TCR down-modulation. , 1998, The Journal of general virology.

[60]  Katsuhiko Mikoshiba,et al.  BANK regulates BCR‐induced calcium mobilization by promoting tyrosine phosphorylation of IP3 receptor , 2002, The EMBO journal.

[61]  A. Guse.  Ca2+ signaling in T-lymphocytes. , 1998, Critical reviews in immunology.