Innate sensing of HIV-1 assembly by Tetherin induces NFκB-dependent proinflammatory responses

Cell Host Microbe. 2012 Nov 15;12(5):633-44. doi: 10.1016/j.chom.2012.10.007.

Abstract

Antiviral proteins that recognize pathogen-specific or aberrantly located molecular motifs are perfectly positioned to act as pattern-recognition receptors and signal to the immune system. Here we investigated whether the interferon-induced viral restriction factor tetherin (CD317/BST2), which is known to inhibit HIV-1 particle release by physically tethering virions to the cell surface, has such a signaling role. We find that upon restriction of Vpu-defective HIV-1, tetherin acts as a virus sensor to induce NFκB-dependent proinflammatory gene expression. Signaling requires both tetherin's extracellular domain involved in virion retention and determinants in the cytoplasmic tail, including an endocytic motif, although signaling is independent of virion endocytosis. Furthermore, recruitment of the TNF-receptor-associated factor TRAF6 and activation of the mitogen-activated protein kinase TAK1 are critical for signaling. Human tetherin's ability to mediate efficient signaling may have arisen as a result of a five amino acid deletion that occurred in hominids after their divergence from chimpanzees.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line, Tumor
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Endocytosis
  • GPI-Linked Proteins / metabolism
  • HEK293 Cells
  • HIV-1 / metabolism*
  • HIV-1 / physiology*
  • HeLa Cells
  • Human Immunodeficiency Virus Proteins / genetics*
  • Humans
  • Inflammation
  • MAP Kinase Kinase Kinases
  • Macaca
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Pan troglodytes
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Pattern Recognition / metabolism
  • Sequence Deletion / genetics
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Ubiquitin-Conjugating Enzymes / genetics
  • Viral Regulatory and Accessory Proteins / genetics*
  • Virus Assembly*
  • Virus Replication

Substances

  • Antigens, CD
  • BST2 protein, human
  • Cytokines
  • GPI-Linked Proteins
  • Human Immunodeficiency Virus Proteins
  • NF-kappa B
  • RNA, Small Interfering
  • Receptors, Pattern Recognition
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6
  • Viral Regulatory and Accessory Proteins
  • vpu protein, Human immunodeficiency virus 1
  • UBE2N protein, human
  • Ubiquitin-Conjugating Enzymes
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7