DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway

Blood. 2011 Jun 16;117(24):6589-99. doi: 10.1182/blood-2011-01-331363. Epub 2011 May 2.

Abstract

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed at high levels on dendritic cells (DCs). This surface molecule acts as an attachment factor for HIV-1 on DCs and contributes to trans- and cis-infection pathways. Moreover, DICR is induced by HIV-1 in CD4(+) T cells and promotes virus replication in this cell type. Nothing is known hitherto about the DCIR-dependent signaling, which is induced following HIV-1 ligation. First, specific pharmacologic inhibitors were tested on HIV-1 binding/entry and, second, specific antisense oligonucleotides targeted, more specifically kinases and phosphatases, were used. Our results show that SHP-1, SHP-2, Syk, and Src kinases (ie, Src, Fyn, and Hck) as well as PKC-α and MAP kinases (ie, Erk1/2 and p38) are all involved in the DCIR-mediated signal transduction pathway triggered by HIV-1. By mutagenesis and through the use of intracellular phosphorylated peptides, we show as well a pivotal role for the tyrosine and threonine residues of the DCIR immunoreceptor tyrosine-based inhibitory motif (ITIM). Our data suggest for the first time an involvement of ITIM domain in HIV-1-mediated signaling events and a relationship between phosphorylation events and DCIR function with respect to HIV-1 biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / physiology
  • Cells, Cultured
  • Disease Progression
  • HIV Infections / genetics*
  • HIV Infections / metabolism
  • HIV Infections / pathology
  • HIV-1 / growth & development
  • HIV-1 / physiology
  • Humans
  • Lectins, C-Type / chemistry*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Lectins, C-Type / physiology*
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology*
  • Phosphorylation / genetics
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Protein Interaction Domains and Motifs / genetics
  • Protein Interaction Domains and Motifs / physiology*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism
  • Receptors, Immunologic / chemistry*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Receptors, Immunologic / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tyrosine / metabolism
  • Tyrosine / physiology
  • Up-Regulation

Substances

  • CLEC4A protein, human
  • Lectins, C-Type
  • Membrane Glycoproteins
  • Protein Kinase Inhibitors
  • Receptors, Immunologic
  • Tyrosine
  • Protein Kinases