USP18 – a multifunctional component in the interferon response

Basters, Anja; Knobeloch, Klaus–Peter; Fritz, Günter

doi:10.1042/bsr20180250

Cited by 74 publications

(66 citation statements)

References 64 publications

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“…After prolonged incubation (72 hours), the level of these genes, except IFI27 and IFI6, has decreased considerably, nearly to the unstimulated basal levels. A similar induction pattern is observed for TRIM14 [8,30], ISG15 [38], USP18 [4], CD317 [6], OAS1, OAS2, OAS3, and OASL [16,31], which are all interferon-dependent genes participating in the antiviral activity of the cells (Fig. 4B).…”

Section: Resultssupporting

confidence: 76%

Fusobacterium nucleatum Promotes Gastric Cancer Aggressiveness through Upregulation of Cell Mobility and Interferon Genes

Hsieh

Tung

Pan

et al. 2020

Preprint

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Background Fusobacterium nucleatum was previously found to become a dominant species in the gastric cancer-associated microbiota of patients from Taiwan. However, the prevalence of Fusobacterium nucleatum infection in gastric cancer has not been examined in a larger patient cohort. In addition, whether Fusobacterium nucleatum elicits a cellular response in gastric cancer remains unknown.Methods A study cohort of resected gastric cancer tissue specimens was examined using nested PCR to detect Fusobacterium nucleatum. In vitro coculture of Fusobacterium nucleatum was carried out to identify the alteration in the expression profile of patient-derived gastric cancer cell line.Results approximately one-third of gastric cancer tissues are positive for Fusobacterium nucleatum. Statistical analysis showed that the risk for Fusobacterium nucleatum infection is increased in late-stage cancer tissue specimens and incurs poorer survival in Helicobacter pylori-positive patients. In vitro coculture experiment shows a drastic interferon response activated only by a high multiplicity of infection, and the response peaks within 24 hours and subsides after 72 hours of incubation. Another set of response genes is the continuous increase of actins and their regulators with prolonged time of incubation, activated by both low and high multiplicity of infection.Conclusions Our data indicates that Fusobacterium nucleatum incites an inflammatory response from the cancer cells and promotes cell mobility, likely

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Section: Resultssupporting

confidence: 76%

Fusobacterium nucleatum Promotes Gastric Cancer Aggressiveness through Upregulation of Cell Mobility and Interferon Genes

Hsieh

Tung

Pan

et al. 2020

Preprint

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“…To better approach the mechanisms involved in the drug effect, we performed a non-targeted transcriptomic analysis and evaluated the level of the genes altered by the different drugs. Among different genes of interest, we selected, at first, USP18, a specific ISG15 isopeptidase and an inhibitor of the interferon type 1 signal [54], which exerts different proteasedependent and independent effects. The ability of USP18 to decrease inflammation has been previously reported in T cell [40,41].…”

Section: Discussionmentioning

confidence: 99%

HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells

et al. 2020

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Objectives Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that lifelong used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance. Methods We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects. Results Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/ sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant.

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“…USP18 is subject to ubiquitindependent proteasomal degradation, which is inhibited by free intracellular ISG15. In this way, USP18 and ISG15 mediate negative feedback on IFNAR signaling, which explains the inflammatory phenotype in the ISG15-deficient patients (20). Remarkably, this stabilizing effect of free ISG15 on USP18 is found in humans, but not in mice (26), in which the affinity of the interaction is lower, likely because of the significant divergence in amino acid sequence of ISG15 between species (7).…”

mentioning

confidence: 99%

“…By comparing phenotypes of Isg15 2/2 mice with those of Ube1l 2/2 mice, in which only the conjugation to substrates, but not the function of free ISG15, is eliminated, the function of free ISG15 can be separated from that of ISGylationdependent mechanisms. Irrespective of its protease function toward ISG15-modified substrates, USP18 represents a major negative regulator of the type I IFN response (20). Therefore, mice lacking USP18 protein expression exhibit phenotypical alterations not directly linked to ISG15.…”

mentioning

confidence: 99%

IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell–Dependent Route

Iglesias-Guimarais

Ahrends

Vries

et al. 2020

The Journal of Immunology

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Type I IFN is produced upon infection and tissue damage and induces the expression of many IFN-stimulated genes (ISGs) that encode host-protective proteins. ISG15 is a ubiquitin-like molecule that can be conjugated to proteins but is also released from cells in a free form. Free, extracellular ISG15 is suggested to have an immune-regulatory role, based on disease phenotypes of ISG15-deficient humans and mice. However, the underlying mechanisms by which free ISG15 would act as a “cytokine” are unclear and much debated. We, in this study, demonstrate in a clinically relevant mouse model of therapeutic vaccination that free ISG15 is an alarmin that induces tissue alert, characterized by extracellular matrix remodeling, myeloid cell infiltration, and inflammation. Moreover, free ISG15 is a potent adjuvant for the CTL response. ISG15 produced at the vaccination site promoted the vaccine-specific CTL response by enhancing expansion, short-lived effector and effector/memory differentiation of CD8+ T cells. The function of free ISG15 as an extracellular ligand was demonstrated, because the equivalents in murine ISG15 of 2 aa recently implicated in binding of human ISG15 to LFA-1 in vitro were required for its adjuvant effect in vivo. Moreover, in further agreement with the in vitro findings on human cells, free ISG15 boosted the CTL response in vivo via NK cells in the absence of CD4+ T cell help. Thus, free ISG15 is part of a newly recognized innate route to promote the CTL response.

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USP18 – a multifunctional component in the interferon response

Cited by 74 publications

References 64 publications

Fusobacterium nucleatum Promotes Gastric Cancer Aggressiveness through Upregulation of Cell Mobility and Interferon Genes

Fusobacterium nucleatum Promotes Gastric Cancer Aggressiveness through Upregulation of Cell Mobility and Interferon Genes

HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells

IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell–Dependent Route

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