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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP3 (2)

NSP5 (1)


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    Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection MESHD

    Authors: Sumana Sanyal; Horace Lee; Deeksha Munnur; Qi Teo; Julian Ho; Wilson Ng; Lewis Siu; Eric Spooner; Hidde Ploegh; Adan Pinto-Fernandez; Andreas Damianou; Benedikt Kessler; Chris Mok

    doi:10.21203/rs.3.rs-63942/v1 Date: 2020-08-22 Source: ResearchSquare

    Interferon stimulated gene 15 ( ISG15 HGNC) is a ubiquitin like modifier frequently induced during virus infections and involved in versatile host defense mechanisms. Not surprisingly, many viruses including SARS-CoV-2 have evolved de-ISGylating activities to antagonize its effect. In this study we compared ISG15 HGNC-driven macrophage responses upon infection by influenza, Zika and SARS-CoV-2 viruses. ISG15 HGNC and its modifying enzymes were upregulated in human macrophages after infection with all three viruses. While influenza and Zika viruses induced cellular ISGylation, SARS-CoV-2 triggered hydrolysis of ISG15 HGNC modifications instead, to generate free, extracellular ISG15 HGNC from macrophages and dendritic cells, but not from bronchial epithelial cells. Extracellular ISG15 HGNC was released independent of the conventional secretory pathway or cell death, but instead, depended on a non-classical autophagy-related secretory process. Increase of extracellular ISG15 HGNC was also reflected in serum samples from COVID-19 MESHD patients. The high ratio of free versus conjugated ISG15 HGNC in SARS-CoV-2 infected cells triggered macrophage polarization towards a M1 phenotype, increased secretion of pro-inflammatory cytokines, e.g. MCP-1 HGNC ( CCL2 HGNC), IL-1 HGNC, TNF HGNC and IL-6 HGNC, and attenuated antigen presentation. Depleting ISG15 HGNC conjugating enzymes Ube1L HGNC and HERC5 HGNC further increased free ISG15 HGNC and exacerbated this effect. We could recapitulate this phenomenon by expressing the wild-type but not the catalytically inactive PLpro PROTEIN de-ISGylating enzyme of SARS-CoV-2. Proteomic analyses of the secretome from SARS-CoV-2 infected macrophages revealed that besides ISG15 HGNC, it displayed significant enrichment in non-classical secretory proteins and inflammatory responses, which was further amplified by free ISG15 HGNC. Collectively, our results indicate that increased proportions of free ISG15 HGNC dramatically alter macrophage responses and is likely a key feature of cytokine storms triggered by highly pathogenic respiratory viruses such as influenza and SARS-CoV-2.

    SARS-CoV-2 proteases cleave IRF3 HGNC and critical modulators of inflammatory pathways ( NLRP12 HGNC and TAB1): implications for disease presentation across species and the search for reservoir hosts.

    Authors: Mehdi Moustaqil; Emma Ollivier; Hsin-Ping Chiu; Paulina Rudolffi-Soto; Sarah Van Tol; Christian Stevens; Akshay Bhumkar; Dominic J.B. Hunter; Alexander N. Freiberg; David Jacques; Benhur Lee; Emma Sierecki; Yann Gambin

    doi:10.1101/2020.06.05.135699 Date: 2020-06-05 Source: bioRxiv

    The genome of SARS-CoV-2 ( SARS2 MESHD) encodes for two viral proteases ( NSP3 PROTEIN NSP3 HGNC/ papain-like protease PROTEIN and NSP5 HGNC NSP5 PROTEIN/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 PROTEIN NSP3 HGNC and NSP5 HGNC NSP5 PROTEIN of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 MESHD NSP3 HGNC NSP3 PROTEIN and NSP5 PROTEIN NSP5 HGNC target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 PROTEIN NSP3 HGNC and NSP5 PROTEIN NSP5 HGNC on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 HGNC NSP3 PROTEIN or NSP5 PROTEIN NSP5 HGNC, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 PROTEIN NSP3 HGNC or NSP5 HGNC NSP5 PROTEIN: IRF-3 HGNC, and NLRP12 HGNC and TAB1, respectively. Direct cleavage of IRF3 HGNC by NSP3 HGNC NSP3 PROTEIN could explain the blunted Type- I IFN response seen during SARS-CoV-2 infection MESHD SARS-CoV-2 infection MESHDs while NSP5 PROTEIN NSP5 HGNC mediated cleavage of NLRP12 HGNC and TAB1 point to a molecular mechanism for enhanced production of IL-6 HGNC and inflammatory response observed in COVID-19 MESHD patients. Surprisingly, both NLRP12 HGNC and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 MESHD and should facilitate the search or development of more effective animal models for severe COVID-19 MESHD. Finally, we discovered that one particular species of bats, Davids Myotis, possesses the five cleavage sites found in humans for NLRP12 HGNC, TAB1 and IRF3 HGNC. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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