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USP18 inhibits Interferon. 64 / 68
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"For instance, human ubiquitin specific peptidase 18 (USP18) negatively regulates type-I IFN signaling by binding to the IFN receptor."
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"Recent data by Zhang and coworkers revealed, however, that USP18 attenuates JAK-STAT signaling, and thereby the type 1 IFN response, in a non enzymatic manner, i.e., by directly competing with JAK1 for binding to the IFNAR2 subunit of the type 1 IFN receptor."
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"These observations established the key role of STAT2 in USP18 mediated inhibition of IFN signaling and moreover suggest that the increased STAT2 levels induced by IFN signaling may further enhance negative feedback by USP18."
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"Besides being an active enzyme, USP18 negatively regulates type I interferon signalling independent of its protease activity [22] (Figure 1)."
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"CRISPR and Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages."
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"Influenza B has evolved a mechanism to directly neutralize ISG15 with its NS1 protein 24 and coronaviruses have a papain-like protease that has deISGylase activity as a strategy to overcome ISG15, 25, 26 indicating the importance of ISG15 in the antiviral response.In addition to its enzymatic activity, USP18 negatively regulates T1 IFN signaling."
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"Given that USP18 suppresses type I IFN signaling and that the mutation in Usp18 Ity9 mice lies within the IFNAR2 binding region of USP18, as well as the importance of type I IFN signaling in bacterial infection, we sought to determine if the IFNAR regulatory function of USP18 is compromised in Usp18 Ity9 mice and whether hyperactivation of type I IFN signaling contributes to the pathogenesis of infection."
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"USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 ( JAK1 ) to the type I interferon receptor ."
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"USP18 regulates antiviral responses by removing ISG15 conjugates and can directly inhibit type I IFN receptor signaling by binding the subunit 2 of the receptor via STAT-2 XREF_BIBR, XREF_BIBR."
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"A majority of these genes are responsible for the regulation and control of early innate inflammation, such as USP18, which disrupts the JAK-STAT pathway downstream of the IFN receptor (43), and TIFAB, which inhibits the activation of the NF-κB pathway (44)."
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"Type 1 IFN responses were partially restored by USP18 knockdown."
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"Induction of USP18 gene expression by candesartan would therefore inhibit interferon signaling in the cells in which this gene is expressed."
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"As these two signals have been thought to have counter-regulatory roles in psoriasis (39), lower USP18 might promote higher IFN response and thus lower TNF dependence, and vice versa, agreeing with the positive correlation with PASI improvement we observed during the course of etanercept treatment."
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"USP18 enzymatic function typically attenuates the immune response by removing interferon-stimulated gene 15 (ISG15) from protein substrates."
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"Indeed, IRF1 uniquely promotes the transcription of the negative regulator USP18 (Forero et al., 2019), which selectively inhibits type I IFN signaling without affecting IFN-λ signaling (Blumer et al., 2017)."
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"However, the suppression of Usp18 has also been described to enhance Ifn responsiveness (Randall et al., 2006)."
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"We have obtained preliminary evidence that, indeed, a catalytically inactive USP18 impairs IFN signaling when highly and stably expressed in naive cells."
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"USP18 Based Negative Feedback Control Is Induced by Type I and Type III Interferons and Specifically Inactivates Interferon alpha Response."
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"It demonstrates that the action of USP18 is predicted to reduce the amplitude of the IFNα2 dose-response curve much more than the corresponding amplitude of the IFNβ dose-response, in agreement with previously reported experimental results (42) and our own experimental analysis (not shown)."
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"One group has proposed that USP18 attenuates IFN alpha signaling regardless of the isopeptidase activity of the protein by competitively displacing Jak1 from its interaction with IFNAR2 XREF_BIBR."
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"Conversely, USP18 overexpression decreased type I and type II IFN responses (Figure 3d) but enhanced IL-17A induced effect on IL36G and TNF-induced effect on DEFB4 (Figure 3e)."
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"On the other hand, the deubiquitinating enzyme USP18 can also directly inhibit type I IFN receptor signaling, thereby suppressing the immune response (Arimoto et al., 2017)."
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"However, USP18 can also directly inhibit type I IFN signaling by 595 binding to STAT2 (Arimoto et al., 2017) and IFNAR2 (Malakhova et al., 2006)."
| DOI
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"However, 438 USP18 can also directly inhibit type I IFN signaling by binding to STAT2 (Arimoto et al., 2017) 439 and IFNAR2 (Malakhova et al., 2006)."
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"BMP-6, upregulated in iLCs only after incubation with poly(I:C)-EVs, induces interferon-stimulated genes, down-regulates USP18 (a suppressor of interferon signaling) and induces an immediate exit from the cell cycle in epithelial stem cells, all favorable conditions during viral challenge ."
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"While we understand well how USP18 recognises ISG15 and deconjugates it from target proteins, it is less clear how USP18 negatively regulates type I IFN signalling on the molecular level."
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"CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages.The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-receptor 2 subunit (IFNAR2)."
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"In addition to its deISGylase activity, USP18 also negatively regulates IFN signaling through association with the IFN receptor."
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"These results are consistent with there being no role for ISGylation (and, thus, for the ability of USP18 to strip ISG15 from its protein conjugates) in the ability of TNF-α and LPS to block type 1 IFN signaling in hepatocytes, and this finding is in agreement with previous data showing that USP18 blocks IFN signaling independent of its enzymatic activity (15)."
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"Correction : Suppression of USP18 Potentiates the Anti-HBV Activity of Interferon Alpha in HepG2.2.15 Cells via JAK and STAT Signaling."
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"USP18 was shown to bind to IFNAR2 and attenuate the JAK-STAT pathway, thereby negatively regulating IFN signaling (Table 1) ."
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"Molecular basis of USP18-mediated inhibition of type I interferon signalling."
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"Whereas ISG15 conjugation has been widely recognized to act antivirally 13, unconjugated ISG15 serves a proviral role by promoting USP18 mediated suppression of type I IFN receptor (IFNAR) signaling XREF_BIBR, XREF_BIBR, XREF_BIBR; this latter function of ISG15 is responsible for over-amplified ISG induction and fortified viral resistance in humans with inherited ISG15 deficiency."
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"A majority of these genes are responsible for the regulation and control of early innate inflammation, such as USP18, which disrupts the JAK-STAT pathway downstream of the IFN receptor (43) , and TIFAB, which inhibits the activation of the NF-k B pathway (44) ."
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"Recent data by Zhang and coworkers (Malakhova et al., 2006) revealed, however, that USP18 attenuates JAK-STAT signaling, and thereby the type 1 IFN response, in a non-enzymatic manner, i.e., by directly competing with JAK1 for binding to the IFNAR2 subunit of the type 1 IFN receptor."
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"USP18 down-regulates type I interferon signaling by blocking the access of Janus associated kinase 1 (JAK1) to the type I interferon receptor."
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"USP18 is thought to inhibit the effect of IFN therapy by reducing its disponibility."
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"As we and others have previously demonstrated that the ISG product USP18 suppresses IFN signaling as a form of negative feedback [XREF_BIBR, XREF_BIBR], reduced ISG mRNA translation under reduced nutrient conditions will be accompanied by sustained transcriptional induction of ISGs, resulting in a prolonged IFN response."
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"USP11 upregulates IkappaB kinase alpha in a ubiquitin independent manner XREF_BIBR, while USP18 has been shown to negatively regulate interferon signalling through protein interactions that are independent of its isopeptidase activity XREF_BIBR."
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"The siRNA knockdown of USP18 in human cells consistently potentiated the ability of IFN to inhibit HCV-RNA replication and infectious virus particle production by a factor of 1-2 log (10)."
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"Suppression of USP18 Potentiates the Anti-HBV Activity of Interferon Alpha in HepG2.2.15 Cells via JAK and STAT Signaling."
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"Given that USP18 attenuates the IFN response, we hypothesized that induction of USP18 allowed HIV‐1 to achieve the balance needed to provide the necessary STAT signaling, without too strong an antiviral response.USP18 is part of the normal negative feedback response that regulates T1 IFN signaling through IFNAR and JAK‐STAT signaling."
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"Moreover, the knockdown of USP18 in hepatoma cells was shown to potentiate the anti-HCV effect of IFN alpha XREF_BIBR."
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"USP18 has been reported to down-regulate type I IFN signaling through binding to IFNAR2 and competing for JAK binding without altering the expression levels of Ifnar2."
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"Whereas ISG15 conjugation has been widely recognized to act antivirally13, unconjugated ISG15 serves a proviral role by promoting USP18 mediated suppression of type I IFN receptor (IFNAR) signaling14, 15, 16; this latter function of ISG15 is responsible for over-amplified ISG induction and fortified viral resistance in humans with inherited ISG15 deficiency."
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"Two downstream ISGs, ISG15 and USP18, negatively regulate interferon induction [100] [101] [102] ."
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"USP18 also negatively regulates type I IFN signaling, independent of its ISG15 isopeptidase activity XREF_BIBR XREF_BIBR."
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"In addition to its isopeptidase activity, USP18 negatively regulates type I and type III IFN signalling by blocking the IFNAR2 subunit of the interferon receptor ."
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"Coiled-coil and DNA binding domains of STAT2 are important for USP18 mediated inhibition of type I IFN signaling."
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"In contrast, a macrophage subset constitutively expresses Usp18, an ISG that inhibits type I IFN responsiveness [XREF_BIBR]."
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"USP18 also interacts with IFNAR2 and STAT2 to block type I interferon signalling in a protease-independent manner."
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"XREF_BIBR This study showed that USP18 or USP20 deficiency significantly inhibited HSV-I or cytosolic DNA activation of both NF-kappaB and IRF3, and type-I IFN and proinflammatory cytokine expression."
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"Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection."
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"Two downstream ISGs, ISG15 and USP18, negatively regulate interferon induction [100–102]."
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"Immune regulatory components whose downregulation improves anti-HIV responses include activated leukocyte cell adhesion molecular (ALCAM) , ubiquitin-specific proteinase 18 (USP18) which negatively regulates type I interferon responses and SAMHD1 in macrophages , and miR-146a that represses antiviral cytokine signaling ."
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"Mechanistically, Usp18 strongly limited the type I interferon response and thereby facilitated replication of the virus."
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"In the liver, the elevated transcription of ISGs includes a number of negative regulators of IFNalpha signalling pathways, such as ubiquitin specific peptidase 18 (USP18), which inhibits further IFN signalling and is thought to contribute to the lack of IFNalpha induced gene induction in treatment nonresponders [XREF_BIBR, XREF_BIBR]."
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"While these patients did not exhibit an increased rate of severe viral disease, they exhibited increased susceptibility to tuberculosis and decreased IFN-gamma production, and their cells were depleted of USP18, which served to downregulate type I IFN signaling by blocking the recycling of ISG15 [XREF_BIBR]."
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"Interestingly, USP18 has been shown to negatively regulate the type I IFN signalling pathway, and its deficiency results in enhanced and prolonged STAT1 phosphorylation XREF_BIBR - XREF_BIBR."
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"Interferon stimulated gene 15 (ISG15)-specific ubiquitin like protease 43 (USP18) abrogates IFN signaling pathways."
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"One prominent member of this family is undoubtedly USP18 which negatively regulates type I IFN signaling by competing with Janus kinase 1 (JAK1) for binding to IFN α/β receptor 2 (IFNAR2) (Malakhova et al., 2006)."
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"USP18 also interacts with IFNAR2 and STAT2 to block type I interferon signalling in a protease-independent manner ."
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"USP18 knockout results in an enhanced response to IFN stimulation in macrophages (Fig. 7)."
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"In addition to its isopeptidase activity, USP18 negatively regulates type I and type III IFN signalling by blocking the IFNAR2 subunit of the interferon receptor 184 ."
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