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Updated: Feb 19, 2026

An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection

Published on: December 10, 2013

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

Narayana Komaravelli1, Maria Ansar2, Roberto P Garofalo3

  • 1Departments of Pediatrics, University of Texas Medical Branch at Galveston, TX, USA.

Free Radical Biology & Medicine
|November 7, 2017
PubMed

Insights

Respiratory syncytial virus (RSV) infection impairs antioxidant defenses in children by degrading the NRF2 protein. A novel RNF4-PML pathway drives this degradation, offering a potential therapeutic target.

Area of Science:

  • Virology
  • Immunology
  • Cellular Biology

Background:

  • Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections in children, with no available vaccines or specific treatments.
  • RSV infection leads to airway inflammation and oxidative damage by suppressing antioxidant enzymes through the degradation of the transcription factor NRF2.
  • While KEAP1 typically mediates NRF2 degradation, RSV utilizes an alternative pathway.

Purpose of the Study:

  • To elucidate the specific mechanism of NRF2 degradation during RSV infection.
  • To identify novel therapeutic targets for mitigating RSV-induced oxidative stress.

Main Methods:

  • Investigated NRF2 degradation pathways in RSV-infected cells.
  • Utilized gene silencing (KEAP1, RNF4, PML) and pharmacological inhibitors (SUMOylation).
  • Assessed NRF2 levels, nuclear localization, transcriptional activity, and association with PML-nuclear bodies (PML-NBs).

Main Results:

  • RSV-induced NRF2 degradation is dependent on the SUMO-specific E3 ubiquitin ligase RNF4, not KEAP1.
  • Blocking SUMOylation or silencing RNF4 restored NRF2 levels and activity.
  • RNF4 associates with PML-NBs, whose formation is interferon-dependent and enhanced during RSV infection.
  • Inhibiting RNF4-PML pathway components reduced NRF2 degradation and increased antioxidant enzyme expression.

Conclusions:

  • The RNF4-PML pathway is a critical regulator of antioxidant defenses during RSV infection.
  • Targeting this pathway holds promise for developing new treatments against RSV-induced oxidative damage.
Keywords:
Antioxidant enzymesKEAP1NRF2PML nuclear bodiesRNF4Respiratory syncytial virusSUMOylationUbiquitination

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