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Nuclear RNF2 inhibits interferon function by promoting K33-linked STAT1 disassociation from DNA

Shuo Liu1, Minghong Jiang1, Wendie Wang1

  • 1Department of Immunology & Centre for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Nature Immunology
|December 16, 2017
PubMed

Insights

Researchers identified RNF2 as a key inhibitor of interferon signaling. This E3 ubiquitin ligase suppresses antiviral responses by modifying STAT1, offering new therapeutic targets for autoimmune diseases.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Prolonged interferon-STAT1 signaling is linked to inflammatory autoimmune disorders.
  • Identifying negative regulators of these pathways is crucial for therapeutic development.

Purpose of the Study:

  • To identify novel negative regulators of interferon-STAT1 signaling.
  • To elucidate the mechanism by which RNF2 inhibits interferon-dependent responses.

Main Methods:

  • High-content screening of 115 mouse RING-domain E3 ligases.
  • Assessing the impact of RNF2 deficiency on interferon-stimulated gene (ISG) expression and antiviral responses.
  • Investigating the molecular interaction between RNF2 and STAT1 using biochemical assays.

Main Results:

  • RNF2 was identified as a potent inhibitor of interferon-dependent antiviral responses.
  • RNF2 deficiency led to enhanced ISG expression and antiviral activity.
  • RNF2 directly binds to STAT1, promoting K33-linked polyubiquitination at K379 and causing dissociation from DNA, thereby suppressing ISG transcription.

Conclusions:

  • RNF2 acts as a nuclear E3 ubiquitin ligase that negatively regulates interferon-STAT1 signaling.
  • RNF2-mediated STAT1 ubiquitination represents a novel mechanism for controlling interferon responses.
  • Targeting RNF2 or its regulatory pathways may offer therapeutic strategies for autoimmune and inflammatory diseases.

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