Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection
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...
| Główni autorzy: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Język: | English |
| Wydane: |
Springer Nature
2021
|
| _version_ | 1826307497089040384 |
|---|---|
| author | Munnur, D Teo, Q Eggermont, D Lee, HHY Thery, F Ho, J van Leur, SW Ng, WWS Siu, LYL Beling, A Ploegh, H Pinto-Fernandez, A Damianou, A Kessler, B Impens, F Mok, CKP Sanyal, S |
| author_facet | Munnur, D Teo, Q Eggermont, D Lee, HHY Thery, F Ho, J van Leur, SW Ng, WWS Siu, LYL Beling, A Ploegh, H Pinto-Fernandez, A Damianou, A Kessler, B Impens, F Mok, CKP Sanyal, S |
| author_sort | Munnur, D |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:03:57Z |
| format | Journal article |
| id | oxford-uuid:e9dc8a80-522e-4c36-9d99-66d39599ca2a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:03:57Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:e9dc8a80-522e-4c36-9d99-66d39599ca2a2022-04-19T09:16:28ZAltered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infectionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e9dc8a80-522e-4c36-9d99-66d39599ca2aEnglishSymplectic ElementsSpringer Nature2021Munnur, DTeo, QEggermont, DLee, HHYThery, FHo, Jvan Leur, SWNg, WWSSiu, LYLBeling, APloegh, HPinto-Fernandez, ADamianou, AKessler, BImpens, FMok, CKPSanyal, SUbiquitin-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. |
| spellingShingle | Munnur, D Teo, Q Eggermont, D Lee, HHY Thery, F Ho, J van Leur, SW Ng, WWS Siu, LYL Beling, A Ploegh, H Pinto-Fernandez, A Damianou, A Kessler, B Impens, F Mok, CKP Sanyal, S Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection |
| title | Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection |
| title_full | Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection |
| title_fullStr | Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection |
| title_full_unstemmed | Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection |
| title_short | Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection |
| title_sort | altered isgylation drives aberrant macrophage dependent immune responses during sars cov 2 infection |
| work_keys_str_mv | AT munnurd alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT teoq alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT eggermontd alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT leehhy alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT theryf alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT hoj alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT vanleursw alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT ngwws alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT siulyl alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT belinga alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT ploeghh alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT pintofernandeza alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT damianoua alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT kesslerb alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT impensf alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT mokckp alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection AT sanyals alteredisgylationdrivesaberrantmacrophagedependentimmuneresponsesduringsarscov2infection |