
| 10.1038/s41590-021-01035-8
http://scihub22266oqcxt.onion/10.1038/s41590-021-01035-8
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Nat+Immunol 2021 ; 22 (11): 1416-1427 Nephropedia Template TP
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Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection #MMPMID34663977Munnur 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 SNat Immunol 2021[Nov]; 22 (11): 1416-1427 PMID34663977show ga
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.|COVID-19/*immunology[MESH]|Cell Differentiation[MESH]|Coronavirus Papain-Like Proteases/metabolism[MESH]|Cytokines/genetics/*metabolism[MESH]|Gene Knockdown Techniques[MESH]|HeLa Cells[MESH]|Humans[MESH]|Immune Evasion[MESH]|Immunity, Innate[MESH]|Inflammation/*immunology[MESH]|Influenza A virus/physiology[MESH]|Influenza, Human/immunology[MESH]|Macrophages/*immunology[MESH]|Pluripotent Stem Cells/cytology[MESH]|SARS-CoV-2/*physiology[MESH]|Ubiquitination[MESH]|Ubiquitins/genetics/*metabolism[MESH]|Zika Virus Infection/immunology[MESH]
  
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