ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity.
Nat Microbiol
; 6(4): 467-478, 2021 04.
Article
in English
| MEDLINE | ID: covidwho-1137784
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Ubiquitins
/
Cytokines
/
Interferon-Induced Helicase, IFIH1
/
Coronavirus Papain-Like Proteases
/
SARS-CoV-2
/
Immunity, Innate
Topics:
Vaccines
Limits:
Animals
/
Humans
Language:
English
Journal:
Nat Microbiol
Year:
2021
Document Type:
Article
Affiliation country:
S41564-021-00884-1
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