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USP18 activates Interferon. 32 / 33
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"Among IFN regulated transcripts, 176 responded similarly in both IFNbeta and IFNgamma treated neurons (XREF_FIG; XREF_SUPPLEMENTARY) and included many genes with known roles in anti-viral defenses and IFN signaling such as Mx1/2, STAT1/2, ISG15, IFIT2, IRF1/7/9, Daxx, PKR, TAP1, and USP18."
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"In humans, genetic loss-of-function mutations in ubiquitin-specific peptidase 18 (USP18), a key negative regulator of type I IFN signaling, results in unrestrained type I IFN signaling in microglia and is associated with multiple and severe developmental neurological abnormalities (intracerebral hemorrhage, ventriculomegaly) along with microgliopathy (Meuwissen et al. 2016)."
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"It is known that IFIH1 (interferon-induced helicase-1), IFI35 (interferon-induced protein 35), and USP18 (ubiquitin-specific peptidases 18) activate the IFN signaling pathway; IFIH1 induces pro-inflammatory cytokines, and type I IFNs respond to viral infections in which they act as innate immune receptors [36,37]."
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"Although distinct reductions in adaptive immunity-related genes were observed, no differences were observed in the mRNA levels of the more general inflammatory cytokines C-C motif chemokine ligand 2 (Ccl2) and C-C motif chemokine ligand 3 (Ccl3) or ubiquitin-specific peptidase 18 (Usp18), which mediates the regulation of the inflammatory response to type 1 interferon (Fig. 3D)."
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"Further investigation with the KEGG pathway enrichment analysis showed those up-regulated genes could cause the activation of the IFN-induced pathway, type II interferon signaling pathway, and regulation of protein ISGylation by the ISG15 deconjugating enzyme USP18 pathway (Figure 4B)."
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"Influenza B has evolved a mechanism to directly neutralize ISG15 with its NS1 protein24 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.27 USP18 is recruited by STAT2 to the type I IFN receptor subunit, IFNAR2, where it binds to IFNAR2 and prevents phosphorylation of JAK1 by blocking the interaction of JAK1 and the IFNAR2 subunit.27, 28, 29 USP18 expression also plays a role in limiting TRAIL‐induced apoptosis and has also been shown to regulate the susceptibility of certain cancer cells to IFN‐α and drug‐induced apoptosis.30, 31
Macrophages play an important role in HIV‐1 as reservoirs and can contribute directly to HIV‐1 pathogenesis.32 HIV‐1 in the ART era can be seen as a chronic disease characterized by chronic immune activation and chronic inflammation with a higher risk of non‐AIDS‐related morbidities and mortalities."
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"The lack of benefit upon induction of nGD in Ifnar1 -/- mice is somewhat surprising and might be due to activation of a compensatory inflammatory mechanism upon interfering with IFN signaling pathways; alternatively, endogenous activation of proteins that block interferon signaling, such as Usp18, might alleviate any beneficial effect of IFN."
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"PROTACS targeting USP18 might represent an interesting approach to specifically degrade USP18 and thus enhance type I IFN signaling.Beside direct destabilization, targeting the interaction of USP18 with important proteins such as STAT2 or ISG15 might constitute an option to interfere with its function.A sophisticated technique to directly study protein–protein interaction within a cellular context is the BRET (Bioluminescence Resonance Energy Transfer) assay where dipole-dipole energy is transferred from a luciferase to a fluorophore."