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

Munnur, Deeksha; Teo, Qi Wen; Eggermont, Denzel; Lee, Horace Hok Yeung; Thery, Fabien; Ho, Julian; Leur, Sophie Wilhelmina van; Ng, Wilfred; Siu, Lewis; Beling, Antje; Ploegh, Hidde L.; Pinto-Fernández, Adán; Damianou, Andreas; Kessler, Benedikt M.; Impens, Francis; Mok, Chris Ka Pun; Sanyal, Sumana

doi:10.1038/s41590-021-01035-8

Cited by 102 publications

(102 citation statements)

References 52 publications

(59 reference statements)

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“…SARS-CoV-2 infection induces ISG15 expression and its conjugation apparatus in induced pluripotent cell-derived (iPSC) macrophages [ 79 ]. MDA5, but not RIG-I activation, has been found to require ISGylation on two lysine residues in its CARD domain.…”

Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

“…Finally, ISG15 can also act as a cytokine, acting on immune cells through LFA-1 to trigger IFN-γ release [ 80 ]. Infection of iPSC macrophages with SARS-CoV-2 causes ISG15 secretion through a novel autophagy-dependent pathway [ 79 ]. In these cells, free ISG15 promotes the release of pro-inflammatory cytokines.…”

Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

“…SARS-CoV-2 opposes MDA5 ISGylation, which (as discussed) is required for RLR signaling [ 61 ]. A proteome-wide study has suggested broader targets of PLpro by comparing detected GG sites in WT and ISG15 knockout IFN-I treated macrophages when PLpro is expressed [ 79 ]. Glycolytic enzymes are found to be ISGylated which is abolished by PLpro expression.…”

Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

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Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

et al. 2022

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Ubiquitylation and ISGylation are protein post-translational modifications (PTMs) and two of the main events involved in the activation of pattern recognition receptor (PRRs) signals allowing the host defense response to viruses. As with similar viruses, SARS-CoV-2, the virus causing COVID-19, hijacks these pathways by removing ubiquitin and/or ISG15 from proteins using a protease called PLpro, but also by interacting with enzymes involved in ubiquitin/ISG15 machinery. These enable viral replication and avoidance of the host immune system. In this review, we highlight potential points of therapeutic intervention in ubiquitin/ISG15 pathways involved in key host–pathogen interactions, such as PLpro, USP18, TRIM25, CYLD, A20, and others that could be targeted for the treatment of COVID-19, and which may prove effective in combatting current and future vaccine-resistant variants of the disease.

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Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

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Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

et al. 2022

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“…We found that IL1β stimulation promoted the overexpression of IRF1 ( Supplementary Figures 8A, B ) and its target ( 14 ) ISG15 ( Supplementary Figures 8C, D ) but not of IRF9 ( Supplementary Figures 8E, F ) in lung cells. Of note, the expression of these targets has been associated with cytokine storm syndrome in COVID-19 patients ( 15 , 16 ). Future high throughput studies should be performed to better understand the interconnection between IL1β and innate immune response in SARS-CoV-2 infection.…”

Section: Resultsmentioning

confidence: 99%

IL1β Promotes TMPRSS2 Expression and SARS-CoV-2 Cell Entry Through the p38 MAPK-GATA2 Axis

et al. 2021

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After the outburst of the SARS-CoV-2 pandemic, a worldwide research effort has led to the uncovering of many aspects of the COVID-19, among which we can count the outstanding role played by inflammatory cytokine milieu in the disease progression. Despite that, molecular mechanisms that regulate SARS-CoV-2 pathogenesis are still almost unidentified. In this study, we investigated whether the pro-inflammatory milieu of the host affects the susceptibility of SARS-CoV-2 infection by modulating ACE2 and TMPRSS2 expression. Our results indicated that the host inflammatory milieu favors SARS-CoV-2 infection by directly increasing TMPRSS2 expression. We unveiled the molecular mechanism that regulates this process and that can be therapeutically advantageously targeted.

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“…The virus also does not actively replicate in myeloid cells [ 80 , 117 ], resulting in fewer templates for transcription and translation - the functional relevance of viral proteins requiring host machinery in myeloid cells thus awaits further study. Recently, reversal of post-translational modifications of downstream effector pathways, such as conjugation of ubiquitin-like protein ISG15 (interferon-stimulated gene 15) [ 118 ], have also been shown to correlate with macrophage hyperpolarization [ 119 ]. Exactly which substrate(s) are responsible for this functional perturbation await future investigation.…”

Section: Myeloid Cell Activation Via Viral/host Protein Interactionsmentioning

confidence: 99%

Myeloid dysregulation and therapeutic intervention in COVID-19

Mao

et al. 2021

Seminars in Immunology

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

Cited by 102 publications

References 52 publications

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

IL1β Promotes TMPRSS2 Expression and SARS-CoV-2 Cell Entry Through the p38 MAPK-GATA2 Axis

Myeloid dysregulation and therapeutic intervention in COVID-19

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