A viral ubiquitin ligase has substrate preferential SUMO targeted ubiquitin ligase activity that counteracts intrinsic antiviral defence

PLoS Pathog. 2011 Sep;7(9):e1002245. doi: 10.1371/journal.ppat.1002245. Epub 2011 Sep 15.


Intrinsic antiviral resistance represents the first line of intracellular defence against virus infection. During herpes simplex virus type-1 (HSV-1) infection this response can lead to the repression of viral gene expression but is counteracted by the viral ubiquitin ligase ICP0. Here we address the mechanisms by which ICP0 overcomes this antiviral response. We report that ICP0 induces the widespread proteasome-dependent degradation of SUMO-conjugated proteins during infection and has properties related to those of cellular SUMO-targeted ubiquitin ligases (STUbLs). Mutation of putative SUMO interaction motifs within ICP0 not only affects its ability to degrade SUMO conjugates, but also its capacity to stimulate HSV-1 lytic infection and reactivation from quiescence. We demonstrate that in the absence of this viral countermeasure the SUMO conjugation pathway plays an important role in mediating intrinsic antiviral resistance and the repression of HSV-1 infection. Using PML as a model substrate, we found that whilst ICP0 preferentially targets SUMO-modified isoforms of PML for degradation, it also induces the degradation of PML isoform I in a SUMO modification-independent manner. PML was degraded by ICP0 more rapidly than the bulk of SUMO-modified proteins in general, implying that the identity of a SUMO-modified protein, as well as the presence of SUMO modification, is involved in ICP0 targeting. We conclude that ICP0 has dual targeting mechanisms involving both SUMO- and substrate-dependent targeting specificities in order to counteract intrinsic antiviral resistance to HSV-1 infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cells, Cultured
  • Gene Expression Regulation, Viral
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / immunology
  • Herpesvirus 1, Human / metabolism*
  • Herpesvirus 1, Human / pathogenicity
  • Humans
  • Immediate-Early Proteins / chemistry
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Nuclear Proteins / metabolism
  • Promyelocytic Leukemia Protein
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Interaction Domains and Motifs
  • Protein Isoforms / metabolism
  • Repressor Proteins / metabolism
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism*
  • Substrate Specificity
  • Trans-Activators
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Viral Proteins / genetics
  • Viral Proteins / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Immediate-Early Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • Protein Isoforms
  • Repressor Proteins
  • SIM1 protein, human
  • SUMO-1 Protein
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Viral Proteins
  • PML protein, human
  • Ubiquitin-Protein Ligases
  • Vmw110 protein, Human herpesvirus 1
  • Proteasome Endopeptidase Complex