TRIM5 is an innate immune sensor for the retrovirus capsid lattice

Nature. 2011 Apr 21;472(7343):361-5. doi: 10.1038/nature09976.

Abstract

TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice and several reports indicate that TRIM5 has a role in signal transduction, but the precise mechanism of restriction is unknown. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13-UEV1A (also known as UBE2N-UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFκB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13-UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-κB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Capsid / chemistry*
  • Capsid / immunology*
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Enzyme Activation
  • HEK293 Cells
  • HIV-1 / chemistry
  • HIV-1 / immunology
  • Humans
  • Immunity, Innate / immunology*
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinases / metabolism
  • NF-kappa B / metabolism
  • Protein Binding
  • Receptors, Pattern Recognition / immunology
  • Receptors, Pattern Recognition / metabolism
  • Retroviridae / chemistry
  • Retroviridae / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism
  • Tripartite Motif Proteins
  • Ubiquitin / metabolism
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Carrier Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Receptors, Pattern Recognition
  • Transcription Factor AP-1
  • Transcription Factors
  • Tripartite Motif Proteins
  • Ubiquitin
  • UBE2N protein, human
  • UBE2V1 protein, human
  • Ubiquitin-Conjugating Enzymes
  • TRIM5 protein, human
  • Ubiquitin-Protein Ligases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7