Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway

Free Radic Biol Med. 2017 Dec;113:494-504. doi: 10.1016/j.freeradbiomed.2017.10.380. Epub 2017 Oct 28.

Abstract

Respiratory syncytial virus (RSV) is the most important cause of viral acute respiratory tract infections and hospitalizations in children, for which no vaccine or specific treatments are available. RSV causes airway mucosa inflammation and cellular oxidative damage by triggering production of reactive oxygen species and by inhibiting at the same time expression of antioxidant enzymes, via degradation of the transcription factor NF-E2-related factor 2 (NRF2). RSV infection induces NRF2 deacetylation, ubiquitination, and degradation through a proteasome-dependent pathway. Although degradation via KEAP1 is the most common mechanism, silencing KEAP1 expression did not rescue NRF2 levels during RSV infection. We found that RSV-induced NRF2 degradation occurs in an SUMO-specific E3 ubiquitin ligase - RING finger protein 4 (RNF4)-dependent manner. NRF2 is progressively SUMOylated in RSV infection and either blocking SUMOylation or silencing RNF4 expression rescued both NRF2 nuclear levels and transcriptional activity. RNF4 associates with promyelocytic leukemia - nuclear bodies (PML-NBs). RSV infection induces the expression of PML and PML-NBs formation in an interferon (INF)-dependent manner and also induces NRF2 - PMN-NBs association. Inhibition of PML-NB formation by blocking IFN pathway or silencing PML expression resulted in a significant reduction of RSV-associated NRF2 degradation and increased antioxidant enzyme expression, identifying the RNF4-PML pathway as a key regulator of antioxidant defenses in the course of viral infection.

Keywords: Antioxidant enzymes; KEAP1; NRF2; PML nuclear bodies; RNF4; Respiratory syncytial virus; SUMOylation; Ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Cell Line, Tumor
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology
  • Gene Expression Regulation
  • Host-Pathogen Interactions*
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oxidative Stress
  • Promyelocytic Leukemia Protein / antagonists & inhibitors
  • Promyelocytic Leukemia Protein / genetics*
  • Promyelocytic Leukemia Protein / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism*
  • Respiratory Syncytial Viruses / genetics*
  • Respiratory Syncytial Viruses / growth & development
  • Respiratory Syncytial Viruses / metabolism
  • Signal Transduction
  • Small Ubiquitin-Related Modifier Proteins / antagonists & inhibitors
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sumoylation
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Ubiquitination
  • Ubiquitins / antagonists & inhibitors
  • Ubiquitins / genetics
  • Ubiquitins / metabolism

Substances

  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • RNA, Small Interfering
  • RNF4 protein, human
  • Reactive Oxygen Species
  • SUMO2 protein, human
  • SUMO3 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Transcription Factors
  • Ubiquitins
  • PML protein, human
  • Proteasome Endopeptidase Complex