HERC5 and the ISGylation Pathway: Critical Modulators of the Antiviral Immune Response

Mathieu, Nicholas A.; Paparisto, Ermela; Barr, Stephen D.; Spratt, Donald E.

doi:10.3390/v13061102

Cited by 38 publications

(31 citation statements)

References 145 publications

(177 reference statements)

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“…In addition, HERC5, RSAD2, and DDX60 are all interferon induced-genes, which play important roles in antiviral response (36)(37)(38)(39). Consistent with our findings, recent studies revealed that the expression level of RSAD2 was markedly increased in the SLE samples compared with controls, which may act as a potential biomarker gene and therapeutic target for the treatment of SLE (40,41).…”

Section: Discussionsupporting

confidence: 91%

Identification and Validation of IFI44 as Key Biomarker in Lupus Nephritis

et al. 2021

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Lupus nephritis (LN) is a common and severe organ manifestation of systemic lupus erythematosus (SLE) and is a major cause of SLE related deaths. Early diagnosis is essential to improve the prognosis of patients with LN. To screen the potential biomarkers associated with LN, we downloaded the gene expression profile of GSE99967 from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was utilized to construct a gene co-expression network and identify gene modules associated with LN. Gene Ontology (GO) analysis was also applied to explore the biological function of genes and identify the key module. Differentially expressed genes (DEGs) were identified and Maximal Clique Centrality (MCC) values were calculated to screen hub genes. Furthermore, we selected promising biomarkers for real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) validation in independent cohorts. Our results indicated that five hub genes, including IFI44, IFIT3, HERC5, RSAD2, and DDX60 play vital roles in the pathogenesis of LN. Importantly, IFI44 may considered as a key biomarker in LN for its diagnostic capabilities, which is also a promising therapeutic target in the future.

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Section: Discussionsupporting

confidence: 91%

Identification and Validation of IFI44 as Key Biomarker in Lupus Nephritis

et al. 2021

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“…In the group of patients with moderate clinical conditions over uninfected control individuals, we observed the expansion of a few sets of biologically grouped genes, with the greatest increase in groups of genes related to cell proliferation. Moreover, the second most represented group of genes was related to antiviral activity (156)(157)(158). On the other hand, in severe over mild cases, the MSCs response was completely different, as they assumed a genotype compatible with a multipurpose protective cell population.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration

et al. 2022

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Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the “cytokine storm” observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.

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“…Several mechanisms have been demonstrated through which free ISG15 and ISGylation possibly contribute to the etiology of human ailments. ISG15 is involved through marking proteins for degradation, antagonizing protein degradation (stabilizing proteins), affecting protein localization, preventing the formation of protein complexes, or regulating immune response(s) [96,126,[136][137][138][139][140][141][142][143][144][145][146][147][148][149][150]. In the current review, we shall focus on the role of the ISG15 pathway in human diseases through protein degradation.…”

Section: The Isg15 Pathway In Human Diseasesmentioning

confidence: 99%

“…After two decades, Ketscher et al reported that inhibition of USP18 deISGylation activity enhances ISGylation and viral resistance [198], supporting the earlier observations by Haas et al Several groups have now endorsed an anti-viral function of ISG15 and ISGylation against murine Gammaherpesvirus, Influenza A and B viruses (IAV), Sindbis virus (SNV), Vaccinia virus, Herpes simplex virus 1 (HSV-1), Chikungunya virus, murine Norovirus, Ebola virus, Dengue virus, and West Nile virus in cell culture, animal, and human studies [96,126,136,142,146,147]. Whether ISG15/ISGylation plays a role in establishing anti-viral immunity against the SARS-CoV-2 virus is unknown; however, there are literature reports implicating the same [145,199,200].…”

Section: Isg15 In Viral and Bacterial Pathogenesismentioning

confidence: 99%

ISG15 and ISGylation in Human Diseases

Mirzalieva

Juncker

Schwartzenburg

et al. 2022

Cells

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Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post‑translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β‑grasp fold in both UBL domains. UBL2 domain has a conserved C‑terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN‑dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a “double-edged sword” for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside.

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HERC5 and the ISGylation Pathway: Critical Modulators of the Antiviral Immune Response

Cited by 38 publications

References 145 publications

Identification and Validation of IFI44 as Key Biomarker in Lupus Nephritis

Identification and Validation of IFI44 as Key Biomarker in Lupus Nephritis

Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration

ISG15 and ISGylation in Human Diseases

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