2020
DOI: 10.1016/j.celrep.2020.107772
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Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins

Abstract: Highlights d ISG15 is released from multiple cell types to signal to LFA-1expressing lymphocytes d Mutational analysis separates ISG15 secretion from LFA-1 binding and ISGylation d Intracellular conjugation of ISG15 negatively modulates its secretion d Viral de-ISGylases, including SARS-CoV-2 PL pro , positively modulate ISG15 secretion

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Cited by 84 publications
(95 citation statements)
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“…Therapeutic inhibition of PLpro would therefore be predicted to have two antiviral effects: restoration of the antiviral effect of ISGylation and inhibition of viral replication by blocking polyprotein cleavage. Further, de-ISGylation by PLpro, through generation of free (unconjugated) ISG15, enhances the secretion and extracellular signaling function of ISG15, which in turn promotes pro-inflammatory cytokine production from cells of the immune system ( 7 ). Therefore, a potential third effect of inhibiting PLpro would be a decrease in pro-inflammatory “cytokine storms” associated with COVID-19 ( 8 ).…”
Section: Main Textmentioning
confidence: 99%
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“…Therapeutic inhibition of PLpro would therefore be predicted to have two antiviral effects: restoration of the antiviral effect of ISGylation and inhibition of viral replication by blocking polyprotein cleavage. Further, de-ISGylation by PLpro, through generation of free (unconjugated) ISG15, enhances the secretion and extracellular signaling function of ISG15, which in turn promotes pro-inflammatory cytokine production from cells of the immune system ( 7 ). Therefore, a potential third effect of inhibiting PLpro would be a decrease in pro-inflammatory “cytokine storms” associated with COVID-19 ( 8 ).…”
Section: Main Textmentioning
confidence: 99%
“…In addition to its function as a ubiquitin-like modifier, free (unconjugated) ISG15 exits cells and signals to LFA-1-expressing cells of the immune system ( e.g ., NK cells, T cells) to release specific cytokines, including IFN-γ and IL-10 ( 7, 12 ), while ISG15 conjugates are retained in cells. Therefore, a secondary effect of PLpro-mediated de-ISGylation is the enhanced secretion of ISG15 ( 7 ). We determined whether 6-TG would block this effect.…”
Section: Main Textmentioning
confidence: 99%
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“…However, it had been described that intracellular ISGylation inhibits the secretion of ISG15, so it seems that that they have separated pathways, one inhibiting the other. Novel de-ISGylases can reverse intracellular ISGylation improving the extracellular ISG15 secretion (66). Consequently, is more plausible that ISG15 coming from lupus NETs is in a free, extracellularly, cytokine-like form accounting, at least in part, for durable pro-in ammatory responses.…”
Section: Discussionmentioning
confidence: 99%
“…SARS-CoV PLpro is a cysteine protease with multiple major functions, including processing of the viral polyprotein chain for viral protein maturation, dysregulating host inflammation responses through deubiquination and impairing the host type I interferon antiviral immune responses by removing ISG15 modifications from host proteins (16)(17)(18). SARS-CoV-2 PLpro (MW = 35.6 kDa) contains two domains including an N-terminal Ubiquitin-like domain and a C-terminal ubiquitin specific protease (USP) domain with implicated catalytic functions of cleaving ubiquitin (Ub) or ISG15 modifications from host proteins (19).…”
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confidence: 99%