IndraLab

Statements

USP18 binds IFNAR2. 115 / 123
3 1 | 38 73
sparser
"The ISG ubiquitin specific peptidase 18 (USP18) binds to IFNAR2, preventing it from recruiting signal transducer and activator of transcription 1 (STAT1)."
25400632
sparser
"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 [58]."
30126853
reach
"Consistent with this, deletion of the STAT2 binding site on IFNAR2 reduced the binding of USP18 to IFNAR2 [50]."
34448086
reach
"These results established that USP18 independently interacts with IFNAR2 and STAT2."
28165510
sparser
"While it was first suggested that USP18 binding to IFNAR2 does not compete with ternary complex formation between IFNAR1, IFNAR2 and IFNα2 [56]."
30126853
sparser
"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 )."
22491252
reach
"We assume that recruitment of USP18 to IFNAR2 via STAT2 promotes the otherwise weak interaction of USP18 with a membrane proximal site of IFNAR2."
28165510
sparser
"Moreover, STAT2 can serve as an adaptor to bridge the interaction between USP18 and IFNAR2, which inhibits ligand binding to the receptor, resulting in decreased receptor dimerization and signaling ( xref )."
31293595
reach
"Gruber and colleagues confirmed this in coimmunoprecipitation experiments in transiently transfected U6A cells overexpressing WT or STAT2-R148Q and USP18, showing a reduced interaction between USP18 and IFNAR2 in the presence of STAT2-R148Q (Fig. 3) [57]."
34448086
sparser
"Specifically, murine USP18 can bind to human IFNAR2 and block type I IFN signaling by competitively interfering with Jak1 binding to the receptor [ xref ]."
31871427
reach
"Among these genes is Usp18, which, in addition to its enzymatic activity, also functions as a negative regulator of IFN-I signaling by binding to IFNAR2 (7)."
34447387
sparser
"6, 20 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."
27809302
sparser
"The effects of USP18 on type I IFN signaling may in part be mediated via binding of USP18 to IFNAR2 (type 1 IFN receptor subunit 2, part of the type I IFN receptor) [ xref ]."
31871427
sparser
"Inhibition of IFN responses by USP18 is independent of cleavage of ISG15; instead, USP18 binds to IFNAR2 and prevents its association with Jak1 ( xref , xref )."
22368279
reach
"(D) The suggested surface areas with which USP18 binds to STAT2 and IFNAR2 are depicted in blue and green, respectively."
30126853
reach
"A comparable loss in USP18 binding to IFNAR2 was obtained in presence of STAT2 upon deletion of the STAT2 binding site on IFNAR2, which was suggested to include at least amino acids 418-444 41."
28165510
reach
"USP18 is recruited by signal transducer and activator of transcription (STAT2) and binds to interferon α/β receptor 2 (IFNAR2) of the interferon receptor complex, displacing Janus kinase 1 (JAK1) and suppressing interferon signalling and the downstream expression of interferon-stimulated genes (ISGs)149."
29769653
sparser
"The IFN-α signal-blocking activity of USP18 is mediated by the binding of USP18 to the intracellular domain of IFNAR2, which prevents the binding of JAK1 to IFNAR227."
28630501
sparser
"Indeed, USP18 binds to IFNAR2 to inhibit type I IFN signaling and subsequently disrupting IFNAR2-JAK1 interaction, thus negatively regulating IFN signaling cascades [ xref ]."
27227879
reach
"Binding of STAT2 and USP18 to IFNAR2 is synergistic, in line with the previous observation that the STAT2-IFNAR2 interaction was strengthened by USP18 33."
28165510
sparser
"The binding of USP18 to IFNAR2 was shown to be independent of dimerisation of IFNAR2 with IFNAR1 [56]."
30126853
sparser
"As a negative regulator of the Jak/STAT signaling, USP18 binds to the intracellular domain of IFNAR2 to block the JAK1-IFNAR2 interaction, leading to the inhibition of signal transduction ( xref )."
34017322
sparser
"The USP18 binds the IFNAR2 subunit, decoupling it from JAK1 and inhibiting the propagation of the next signal."
33869112
sparser
"Since STAT2 itself constitutively interacts with IFNAR2 xref , xref , xref , we aimed to further examine whether interaction between USP18 and IFNAR2 was affected by STAT2."
28165510
sparser
"The importance of STAT2 for USP18 recruitment could also be verified by live cell micropatterning: while no binding of USP18 to micropatterned IFNAR2 was detectable in U6A cells, a strong increase in contrast after complementation with STAT2 was observed ( xref )."
28165510
sparser
"The USP18:IFNAR2 interaction is substantially impaired (although not completely abolished) in the absence of STAT2 [50]."
34448086
reach
"Based on our previous report 21 and the results presented above, USP18 interacts with both IFNAR2 and STAT2."
28165510
biogrid
No evidence text available
27716962
reach
"The recruitment of STAT2 and USP18 to IFNAR2, C-terminally truncated at position 375, was strongly reduced (XREF_FIG and XREF_SUPPLEMENTARY)."
28165510
reach
"Inhibition of IFN responses by USP18 is independent of cleavage of ISG15; instead, USP18 binds to IFNAR2 and prevents its association with Jak1."
22368279
sparser
"In addition to being an active enzyme, USP18 can bind to the intracellular part of IFNAR2 and compete with the binding of JAK1 to the receptor, which results in negative regulation of IFNAR signaling independently of its protease activity (117)."
34707613
reach
"Regarding USP18 and IFNAR2 interaction, peptides comprising aa 1-112, 1-242, and 313-372, but not aa 51-242, 113-242, and 243-312 of USP18 co-immunoprecipitated with the intracellular domain (ICD) of IFNAR2 (XREF_SUPPLEMENTARY)."
28165510
sparser
"The IFN-α signal-blocking activity of USP18 is mediated by the binding of USP18 to the intracellular domain of IFNAR2, which prevents the binding of JAK1 to IFNAR2 xref ."
28630501
sparser
"USP18’s interaction with IFNAR2 also interfered with IFNAR2’s ability to recruit IFNAR1, hindering IFN I signaling [ xref ]."
31208841
sparser
"USP18 specifically interacts with the IFNAR2 subunit to inhibit the interaction between JAK and the IFN receptor ( xref )."
30671058
sparser
"The USP18-IFNAR2 interaction makes it so that only higher affinity ligands such as IFNβ are able to recruit IFNAR1 into the receptor complex, making the cell less responsive to weaker affinity type I IFNs (76, 77)."
33408718
biogrid
No evidence text available
16710296
sparser
"It has been resported that mouse USP18 interacts with IFNAR2 to negatively regulate type I IFN signaling [ xref – xref ]."
26193702
reach
"The binding of USP18 to IFNAR2 was shown to be independent of dimerisation of IFNAR2 with IFNAR1 [56]."
30126853
sparser
"Since USP18 binds to IFNαR2, but not JAK1, we assume that the dysregulation of STAT1 phosphorylation by USP18 attachment occurs at the level of the IFNαR2 docking site for STAT1, where activated JAK1 phosphorylates STAT1."
27716962
reach
"While it was first suggested that USP18 binding to IFNAR2 does not compete with ternary complex formation between IFNAR1, IFNAR2 and IFNα2 [56]."
30126853
sparser
"Binding of USP18 to the cytoplasmic domain of IFNAR2 does not affect the binding affinity of the extracellular domain, which binds IFNs independent of the membrane and the transmembrane domain (JP, unpublished results)."
23046138
sparser
"Under specific circumstances, USP18 binds to IFNAR2, one the subunit of the IFNAR dimer, and compete with JAK preventing proper activation of the pathway [ xref ]."
31658294
sparser
"In HeLa cells, the endogenous expression level of STAT2 was sufficient to yield significant binding of USP18 bound to micropatterned IFNAR2 ( xref )."
28165510
sparser
"Taken together, these findings indicate that aa 36-51 and 313-371 of USP18 are critical for the USP18-IFNAR2 interaction and that aa 51-112 and 303-312 of USP18 are important for the USP18-STAT2 interaction."
28165510
reach
"STAT2 has been described as an adaptor that mediates USP18 binding to IFNAR2 [XREF_BIBR]."
31771763
sparser
"Using molecular, biochemical, and genetic approaches, we demonstrate that Ubp43 specifically binds to the IFNAR2 receptor subunit and inhibits the activity of receptor-associated JAK1 by blocking the interaction between JAK and the IFN receptor."
16710296
sparser
"Our data suggest that USP18 is recruited to IFNAR2 via its interaction with the STAT2 CC and DB domains to allow an additional interaction of USP18 with the membrane-proximal domain of IFNAR2 ( xref ), which probably causes JAK1 dissociation xref ."
28165510
sparser
"It has been reported that USP18 specifically binds to the IFNAR2 receptor subunit, inhibits the interaction between JAK and the IFN receptor, and attenuates the activity of receptor-associated JAK1 xref ."
26240016
reach
"The ISG ubiquitin specific peptidase 18 (USP18) binds to IFNAR2, preventing it from recruiting signal transducer and activator of transcription 1 (STAT1)."
25400632
sparser
"In STAT2-deficient U6A cells, the USP18-IFNAR2 interaction was up to 10-fold enhanced upon expression of STAT2 ( xref )."
28165510
sparser
"Consistent with this, deletion of the STAT2 binding site on IFNAR2 reduced the binding of USP18 to IFNAR2 [50]."
34448086
reach
"Interestingly, direct interaction between USP18 and IFNAR2 have been shown to contribute in the negative regulation of type I IFN independently of USP18-deISGylase/isopeptidase activity (Malakhova et al., 2006)."
30483224
sparser
"By preventing USP18 degradation ISG15 stabilizes the interaction between IFNAR2 and USP18 ( xref )."
32492472
reach
"Thus, USP18 binding to IFNAR2 stabilizes the constitutive STAT2-IFNAR2 interaction by a factor of ~ 8."
25385185
sparser
"Regarding USP18 and IFNAR2 interaction, peptides comprising aa 1-112, 1-242, and 313-372, but not aa 51-242, 113-242, and 243-312 of USP18 co-immunoprecipitated with the intracellular domain (ICD) of IFNAR2 ( xref )."
28165510
reach
"Indeed, USP18 binds to IFNAR2 to inhibit type I IFN signaling and subsequently disrupting IFNAR2-JAK1 interaction, thus negatively regulating IFN signaling cascades [XREF_BIBR]."
27227879
sparser
"The USP18-IFNAR2 interaction makes it so that only higher affinity ligands such as IFNβ are able to recruit IFNAR1 into the receptor complex, making the cell less responsive to weaker affinity type I IFNs ( xref , xref )."
33408718
sparser
"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 ]."
30126853
sparser
"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."
27809302
sparser
"Consistent with previous results xref , our experiments confirmed that the N- and C-terminal regions of USP18 directly interact with IFNAR2."
28165510
sparser
"This effect is independent of the catalytic activity of USP18, which suggests that USP18 binding to IFNAR2 ( xref ; xref ) directly interferes with complex stabilization via the intracellular domains."
26008745
reach
"Mapping the STAT2 and USP18 binding to IFNAR2 by cell micropatterning of further deletions and mutations (XREF_SUPPLEMENTARY) confirmed aa 418-444 of IFNAR2 as a minimal interaction site for STAT2 and USP18."
28165510
reach
"USP18 directly binds to IFN-alpha and beta receptor 2 (IFNAR2) in human KT-1 cells and, by competing for JAK1 binding, inhibits type I IFN signaling."
23825189
sparser
"USP18 interacts with IFNAR2 to prevent JAK1 from interacting with IFNAR2, and thus, USP18 suppresses signal transmission from IFN-α binding [ xref , xref ]."
32276399
sparser
"The mechanism by which acetaldehyde downregulates pSTAT1 is related to an enhanced interaction between IFNαR2 and USP18 that finally dysregulates the cross-talk between the IFN receptor on the cell surface and STAT1."
27716962
reach
"USP18 's interaction with IFNAR2 also interfered with IFNAR2 's ability to recruit IFNAR1, hindering IFN I signaling [XREF_BIBR]."
31208841
hprd
No evidence text available
16710296
sparser
"This can be explained by the substantially higher binding affinity of IFNβ toward IFNAR1, corroborating the notion that binding of USP18 to the cytoplasmic domain of IFNAR2 interferes with ternary complex formation."
23046138
sparser
"The USP18-IFNAR2 interaction makes it so that only higher affinity ligands such as IFNb are able to recruit IFNAR1 into the receptor complex, making the cell less responsive to weaker affinity type I IFNs (76, 77) . subtypes may be able to signal through alternative pathways, in spite of or, more likely, because of possessing lower binding affinity."
33408718
sparser
"Importantly, STAT2 plays a critical role as an adaptor protein by supporting binding of USP18 to IFNAR2 ( xref ) ( xref )."
31836668
reach
"This action appears to be independent of its protease activity and mediated by the specific binding of USP18 to IFNAR2, which then blocks the interaction between JAK1 and the IFN receptor and results in inhibition of the downstream phosphorylation cascade XREF_BIBR."
21886806
reach
"It has been resported that mouse USP18 interacts with IFNAR2 to negatively regulate type I IFN signaling [XREF_BIBR - XREF_BIBR]."
26193702
sparser
"The binding of USP18 to IFNAR2 was shown to be independent of dimerisation of IFNAR2 with IFNAR1 [ xref ]."
30126853
sparser
"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
sparser
"The USP18 binds the IFNAR2 subunit, decoupling it from JAK1 and inhibiting the propagation of the next signal."
| PMC
sparser
"Gruber and colleagues confirmed this in coimmunoprecipitation experiments in transiently transfected U6A cells overexpressing WT or STAT2-R148Q and USP18, showing a reduced interaction between USP18 and IFNAR2 in the presence of STAT2-R148Q (Fig. 3) [57]."
34448086
sparser
"Interestingly, the association of USP18 with IFNAR2 is not dependent on the dimerization of IFNAR2 with IFN α/β receptor 1 (IFNAR1) [ xref ]."
32957626
sparser
"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."
25385185
sparser
"USP18’s interaction with IFNAR2 also interfered with IFNAR2’s ability to recruit IFNAR1, hindering IFN I signaling [46]."
31208841
sparser
"USP18 can specifically bind to the IFNAR2 receptor subunit, to disrupt the interaction between JAK and the IFN receptor, and to inhibit the phosphorylation of receptor-associated JAK1 xref ."
26240016
sparser
"This UBP43 action is achieved through a direct interaction between UBP43 and IFNAR2, a subunit of type I IFN receptor."
20153823
sparser
"UBP43 binds to IFNAR2 and inhibits the interaction between JAK1 and IFNAR2; this is independent of its isopeptidase activity."
18802094
sparser
"USP18 binding to IFNAR2 stabilizes the interaction of STAT2 with IFNAR2 ( xref ) and inhibits IFN-α binding ( xref , xref )."
33552080
reach
"We next examined IFNAR2 independent interaction of STAT2 and USP18 in IFNAR2 deficient U5A cells by using cell micropatterning."
28165510
reach
"Unlike SOCS proteins, USP18 binds IFNAR2 to block the activation of the JAK-STAT pathway induced by IFNα (Francois-Newton et al., 2011) ."
35317429
reach
"Taken together, our data suggest that USP18 simultaneously interacts with IFNAR2 via STAT2 in the membrane distal region and directly in the membrane proximal region (XREF_FIG)."
28165510
reach
"USP18 binding to IFNAR2 stabilizes the interaction of STAT2 with IFNAR2 and inhibits IFN-alpha binding."
33552080
sparser
"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."
25826356
reach
"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 [58]."
30126853
sparser
"Regardless of its enzymatic activity, UBP43 directly interacts with the IFNAR2 subunit of the IFN-α/β receptor such that UBP43 inhibits the activation of receptor-associated JAK1 by blocking the interaction between JAK1 and IFNAR2 [ xref ]."
22683641
sparser
"Thus, USP18 binding to IFNAR2 stabilizes the constitutive STAT2–IFNAR2 interaction by a factor of ∼8."
25385185
reach
"USP18 interacts with IFNAR2 to prevent JAK1 from interacting with IFNAR2, and thus, USP18 suppresses signal transmission from IFN-alpha binding [XREF_BIBR, XREF_BIBR]."
32276399
reach
"USP18 binds STAT2 and IFNAR2, displacing JAK1 from the cytoplasmic domain of IFNAR2 and inducing a conformational change in the IFN-IFNAR1-IFNAR2 complex, leading to impaired signal transduction (left)."
34448086
reach
"Since STAT2 itself constitutively interacts with IFNAR2 XREF_BIBR, XREF_BIBR, XREF_BIBR, we aimed to further examine whether interaction between USP18 and IFNAR2 was affected by STAT2."
28165510
reach
"USP18's interaction with IFNAR2 also interfered with IFNAR2's ability to recruit IFNAR1, hindering IFN I signaling [46] ."
31208841
reach
"The reported interactions between USP18 and IFNAR2 as well as STAT2 remain to be characterised biochemically and structurally."
30126853
sparser
"The R148 residue is located in the CCD of STAT2, a region previously implicated in the interactions with both USP18 [50] and IFNAR2 [34]."
34448086
reach
"This effect is independent of the catalytic activity of USP18, which suggests that USP18 binding to IFNAR2 directly interferes with complex stabilization via the intracellular domains."
26008745
sparser
"This domain facilitates USP18 binding to the intracellular domain of the IFNAR2 subunit leading to the suppression of interferon induced Jak/STAT signaling."
29285303
sparser
"The mechanism by which Ach down-regulates pSTAT1 is related to an enhanced interaction between IFNαR2 and USP18 that finally dysregulates the cross talk between the IFN receptor on the cell surface and STAT1."
27716962
sparser
"A comparable loss in USP18 binding to IFNAR2 was obtained in presence of STAT2 upon deletion of the STAT2 binding site on IFNAR2, which was suggested to include at least amino acids 418-444 xref ."
28165510
sparser
"We assume that recruitment of USP18 to IFNAR2 via STAT2 promotes the otherwise weak interaction of USP18 with a membrane-proximal site of IFNAR2."
28165510
reach
"USP18 binds to IFNAR2 by competing with Jak1, thereby limits the activity of STATs and suppresses IFN response."
29285303
sparser
"Binding of IFNAR2 to UBP43 interferes with the interaction between JAK and the receptor, leading to the inhibition of downstream phosphorylation cascade and other signaling events."
20153823
sparser
"STAT2 has been described as an adaptor that mediates USP18 binding to IFNAR2 [ xref ]."
31771763
sparser
"While it was first suggested that USP18 binding to IFNAR2 does not compete with ternary complex formation between IFNAR1, IFNAR2 and IFNα2 [ xref ]."
30126853
sparser
"This isopeptidase-independent activity is mediated by the binding of USP18 to the intracellular domain of IFNAR2, which prevents the binding of JAK1."
24555472
biogrid
No evidence text available
16710296
sparser
"Unlike SOCS proteins, USP18 binds IFNAR2 to block the activation of the JAK-STAT pathway induced by IFNα (Francois-Newton et al., 2011) ."
35317429
sparser
"These results suggest that aa 1-51 and aa 313-372 of USP18 are important for the IFNAR2-USP18 interaction."
28165510
sparser
"Overall, we favor a model whereby the interaction of USP18 with IFNAR2 ( xref and our data) may lead to a re-organization of the architecture of the type I IFN receptor."
21779393
reach
"The USP18 binds the IFNAR2 subunit, decoupling it from JAK1 and inhibiting the propagation of the next signal."
| PMC
sparser
"USP18 interacts with IFNAR2 to prevent JAK1 from interacting with IFNAR2, and thus, USP18 suppresses signal transmission from IFN-α binding [47,48]."
32276399
sparser
"Interestingly, direct interaction between USP18 and IFNAR2 have been shown to contribute in the negative regulation of type I IFN independently of USP18-deISGylase/isopeptidase activity ( xref )."
30483224