A viral E3 ubiquitin ligase produced by herpes simplex virus 1 inhibits the NLRP1 inflammasome

J Exp Med. 2024 Aug 5;221(8):e20231518. doi: 10.1084/jem.20231518. Epub 2024 Jun 11.

Abstract

Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0's cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans.

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Animals
  • HEK293 Cells
  • Herpes Simplex / immunology
  • Herpes Simplex / metabolism
  • Herpes Simplex / virology
  • Herpesvirus 1, Human* / physiology
  • Humans
  • Immediate-Early Proteins / metabolism
  • Inflammasomes* / metabolism
  • Keratinocytes / metabolism
  • Keratinocytes / virology
  • NLR Proteins* / metabolism
  • Ubiquitin-Protein Ligases* / metabolism
  • Virus Replication

Substances

  • Inflammasomes
  • Ubiquitin-Protein Ligases
  • NLRP1 protein, human
  • NLR Proteins
  • Adaptor Proteins, Signal Transducing
  • Vmw110 protein, Human herpesvirus 1
  • Immediate-Early Proteins