» Articles » PMID: 33727702

ISG15-dependent Activation of the Sensor MDA5 is Antagonized by the SARS-CoV-2 Papain-like Protease to Evade Host Innate Immunity

Overview
Journal Nat Microbiol
Date 2021 Mar 17
PMID 33727702
Citations 162
Authors
Affiliations
Soon will be listed here.
Abstract

Activation of the RIG-I-like receptors, retinoic-acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15, the mechanistic roles of which in innate immunity still remain enigmatic. In the present study, we report that ISG15 conjugation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISGylation of the caspase activation and recruitment domains of MDA5 promotes its oligomerization and thereby triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease of SARS-CoV-2, a recently emerged coronavirus that has caused the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a key immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19.

Citing Articles

Anti-interferon armamentarium of human coronaviruses.

Khatun O, Kaur S, Tripathi S Cell Mol Life Sci. 2025; 82(1):116.

PMID: 40074984 PMC: 11904029. DOI: 10.1007/s00018-025-05605-z.


Hepatitis B virus confers innate immunity evasion through hepatitis B virus-miR-3 down-regulation of cGAS-Sting-IFN signaling.

Xu Z, Gao J, He Y, Xiao X, Gong G, Zhang M World J Hepatol. 2025; 17(2):99292.

PMID: 40027574 PMC: 11866139. DOI: 10.4254/wjh.v17.i2.99292.


Viral tolerance enabled by a bat-specific genomic tweak.

Zhu J, Gack M Nature. 2025; 638(8050):326-327.

PMID: 39881171 DOI: 10.1038/d41586-025-00081-8.


Bat genomes illuminate adaptations to viral tolerance and disease resistance.

Morales A, Dong Y, Brown T, Baid K, Kontopoulos D, Gonzalez V Nature. 2025; 638(8050):449-458.

PMID: 39880942 PMC: 11821529. DOI: 10.1038/s41586-024-08471-0.


Strategies Used by SARS-CoV-2 to Evade the Innate Immune System in an Evolutionary Perspective.

Fan H, Tian M, Liu S, Ye C, Li Z, Wu K Pathogens. 2025; 13(12.

PMID: 39770376 PMC: 11677916. DOI: 10.3390/pathogens13121117.


References
1.
Liu G, Gack M . Distinct and Orchestrated Functions of RNA Sensors in Innate Immunity. Immunity. 2020; 53(1):26-42. PMC: 7367493. DOI: 10.1016/j.immuni.2020.03.017. View

2.
Wu J, Chen Z . Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol. 2014; 32:461-88. DOI: 10.1146/annurev-immunol-032713-120156. View

3.
Chow K, Gale Jr M, Loo Y . RIG-I and Other RNA Sensors in Antiviral Immunity. Annu Rev Immunol. 2018; 36:667-694. DOI: 10.1146/annurev-immunol-042617-053309. View

4.
Schlee M . Master sensors of pathogenic RNA - RIG-I like receptors. Immunobiology. 2013; 218(11):1322-35. PMC: 7114584. DOI: 10.1016/j.imbio.2013.06.007. View

5.
Rehwinkel J, Gack M . RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol. 2020; 20(9):537-551. PMC: 7094958. DOI: 10.1038/s41577-020-0288-3. View