IndraLab
Statements
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"The IFN-mediated activation of the Jak-STAT pathway is tightly regulated by various cellular factors such as SOCS family members, USP18, the protein phosphatase 2A (PP2A), and protein inhibitors of STAT (PIAS).[ xref ] Along those lines, SOCS1 and SOCS3 transcriptional expression in hepatocytes remains detectable for only a short period of time upon alfa treatment indicating that by inhibiting Janus kinases both proteins are likely responsible for early termination of STAT activation.[ xref ] In addition, the sustained up-regulation of USP18 was associated with a long-lasting refractory state to IFN-α stimulation in hepatocytes and other primary human cells.[ xref ] The specific interaction of USP18 with IFNAR2 selectively affects IFN—induced signaling while having a marginal effect on other classes of IFNs, including type III IFNs."
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"USP18 binds to IFNAR2 and thereby inhibits downstream substrate phosphorylation (Malakhova et al , xref ), while SOCS proteins act at the receptor level directly inhibiting formation of the active receptor‐IFN complex (aRecIFN) by inhibiting JAK family members (Chen et al , xref )."
| PMC
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"Furthermore, Usp18 functions in the type I IFN pathway by down-regulating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway independently of its isopeptidase activity through an interaction between Usp18 and the IFNAR2 subunit of the type I IFN receptor complex, while neither IFNAR1 nor IFNGR1 (type II IFN) receptor subunits were able to interact with Usp18 ( xref )."
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"Consistent with previous reports [ xref ], our data show that ISG15 appears dispensable for the interaction of USP18 with IFNAR2; therefore, we hypothesise that the ISG15's contribution may be essential for further stabilizing the USP18‐inhibitory complex, for recruiting yet‐to‐be identified interaction partners of USP18 or promoting a conformational change in USP18 necessary for its inhibitory activity (or a combination thereof)."
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"In STAT2-deficient cells, the USP18-mediated inhibition of type I interferon signalling was reduced and the interaction between IFNAR2 and USP18 was weakened pointing to an essential role of STAT2 in USP18-mediated inhibition of the type I interferon signalling pathway [ xref ]."
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"This function is independent of its activity as an isopeptidase. xref USP18 itself is upregulated in the presence of IFNs through the activation of the JAK-STAT signaling pathway. xref , xref In turn, USP18 specifically binds to the IFNAR2 subunit and thereby prevents the phosphorylation of JAK1 by blocking the interaction of JAK1 and the IFNAR2 subunit and downstream signaling. xref This phenotype cannot be explained by the delSGylation activity of USP18, because deleting ISG15 or the ISGylation-activating enzyme UBE1L in mice did not reverse the phenotype in Usp18 -deficient mice. xref , xref , xref However, unlike mice, the presence of ISG15 in human cells is essential to stabilize USP18 and guarantee the function of this protein as IFN-I suppressor. xref This means that, in humans, ISG15 can also be considered as a good target protein by which we can strengthen IFN-I signaling and reduce viral replication."
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"Based on this approach, we succeeded in addressing several fundamental concepts in cytokine signaling for the IFNAR as a model system: (a) ligand-induced heterodimerization of IFNAR1 and IFNAR2 in contrast to currently debated modes of preassembled subunits ( xref ) was clearly demonstrated; (b) relatively stable association of the corresponding Jaks with the cytosolic receptor domains was directly shown; (c) stimulation-independent, transient binding of STAT2 to IFNAR2 and the recruitment of STAT1 via STAT2 could be shown as well as increased STAT recruitment to the activated signaling complex; and (d) the interaction of the negative feedback regulator USP18 with IFNAR2 and a novel role in modulating STAT recruitment could be identified."
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"After recruitment by signal transducer and activator of transcription (STAT) 2, USP18 interacts with interferon alpha and beta receptor subunit 2 (IFNAR2) through its C-terminal domain and competes with Janus kinase (JAK)1 for binding and transducing signals to inhibit type I IFN (IFN-I)-mediated effects xref , xref ."
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"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway [89]."