Related Experiment Video

Updated: Nov 12, 2025

Monitoring Activation of the Antiviral Pattern Recognition Receptors RIG-I And PKR By Limited Protease Digestion and Native PAGE
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Monitoring Activation of the Antiviral Pattern Recognition Receptors RIG-I And PKR By Limited Protease Digestion and Native PAGE

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ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host

GuanQun Liu1,2, Jung-Hyun Lee1,2, Zachary M Parker2

  • 1Florida Research and Innovation Center, Cleveland Clinic, Port St Lucie, FL, USA.

Nature Microbiology
|March 17, 2021
PubMed

Insights

ISG15 conjugation is vital for MDA5-mediated antiviral immunity against viruses. SARS-CoV-2 protease antagonizes this response, revealing a key viral immune evasion strategy.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • RIG-I-like receptors (RLRs) initiate antiviral responses by upregulating interferon-stimulated genes (ISGs).
  • The precise function of ISG15 in innate immunity remains unclear.
  • ISG15 is an ISG upregulated upon RLR activation.

Purpose of the Study:

  • To elucidate the role of ISG15 conjugation in MDA5-mediated antiviral immunity.
  • To investigate the interaction between ISG15, MDA5, and SARS-CoV-2.

Main Methods:

  • Investigated ISG15 conjugation to MDA5.
  • Assessed MDA5 activation and oligomerization.
  • Studied the effect of SARS-CoV-2 papain-like protease on MDA5 activity.

Main Results:

  • ISG15 conjugation is essential for MDA5 activation and subsequent antiviral responses.
  • ISGylation of MDA5's caspase activation and recruitment domains promotes its oligomerization.
  • SARS-CoV-2 papain-like protease de-ISGylates MDA5, antagonizing the antiviral response.

Conclusions:

  • ISG15 plays a critical role in MDA5-mediated antiviral immunity against various viruses.
  • SARS-CoV-2 employs a mechanism to evade host antiviral defenses by targeting ISG15-MDA5 interaction.
  • This finding offers potential targets for developing novel antivirals and vaccines against SARS-CoV-2.

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