Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection.
Nat Immunol
; 22(11): 1416-1427, 2021 11.
Article
in English
| MEDLINE | ID: covidwho-1475314
ABSTRACT
Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Ubiquitins
/
Cytokines
/
SARS-CoV-2
/
COVID-19
/
Inflammation
/
Macrophages
Limits:
Humans
Language:
English
Journal:
Nat Immunol
Journal subject:
Allergy and Immunology
Year:
2021
Document Type:
Article
Affiliation country:
S41590-021-01035-8
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