IndraLab

Statements

ISG15 affects USP18
12 1 | 99 140
ISG15 binds USP18.
12 1 | 50 140
ISG15 binds USP18. 10 / 194
12 1 | 47 134
reach
"In humans, binding of ISG15 to USP18 prevents USP18 degradation, amplifying the inhibition of IFN signaling."
37115698
reach
"We hypothesized that differential catalytic activity across species may be related to substrate affinity.53 Although the catalytic site of USP18 is well conserved between mice and humans, ISG15 sequences vary.52 54 To compare interactions between USP18 and ISG15, we performed a competitive inhibition experiment with cross-species enzyme/substrate pairs."
38632987
reach
"The ability of non-fluorescent ISG15 substrate to compete with fluorescent mISG15-Rho110 substrate is a proxy for affinity between non-fluorescent ISG15 and USP18."
38632987
biogrid
No evidence text available
35962463
sparser
"The association of ISG15 with USP18 interrupts the interaction of USP18 with S-phase kinase-associated protein 2 (SKP2), inhibiting the proteasomal degradation of USP18, which is essential for negative feedback regulation of IFN signaling and prevention of autoinflammation xref , xref ."
36319753
sparser
"USP18 also has enzymatic activity in removing the covalently conjugated 15kDa protein, encoded by interferon-stimulated gene 15 ( ISG15 ), from its targets in a process called de-ISGylation. xref Finally, independent of its affinity for ISGylated proteins, USP18 also binds free ISG15, which protects USP18 against proteasomal degradation, thereby enhancing its negative regulatory capacity. xref "
31940699
sparser
"We recently demonstrated that human free intracellular ISG15 binds USP18, a negative regulator of IFN-α/β signalling."
27193971
reach
"However, the noncovalent binding of free intracellular ISG15 with USP18 inhibits SKP2-mediated USP18 degradation [75,77]."
38675828
sparser
"In humans, ISG15 binds to USP18, increasing its stability and leading to a decrease in IFN-α/β signaling."
30428561
sparser
"Furthermore, we demonstrate that there is a species-specific interaction between ISG15 and USP18."
27193971
UBL binds ISG15 and USP18. 3 / 3
| 3
sparser
"The crystal structure of mouse USP18 in complex with mouse ISG15 displayed extensive interaction between the ISG15 C-terminal Ubl domain and the palm and thumb domain of USP18 (Basters et al., xref )."
32039148
sparser
"Structural data demonstrated that only the ISG15 C-terminal but not the N-terminal UBL domain binds USP18."
32039148
sparser
"However, only the C-terminal Ubl domain of ISG15 interacts with USP18 whereas no interaction between the N-terminal Ubl domain and USP18 was detected and the presence of the N-terminal domain of ISG15 is dispensable for the deISGylation activity of USP18."
30126853
USP18 binds ISG15 and Arg151. 1 / 1
| 1
reach
"A structural overlay of unbound USP18 and the USP18 and ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short alpha-helix of unbound USP18 (XREF_FIG)."
28165509
ISG15 binds USP18 and FASLG. 1 / 1
| 1
sparser
"To confirm that the expected complex between ISG15 and UBP43 formed in APL cells, NB4-S1 cell lysates were immunoprecipitated with an anti-HA antibody, before immunoblotting independently with an anti-HA or the anti-UBP43-1 antibody."
20935222
USP18 binds ISG15 and UBA7. 1 / 1
| 1
sparser
"Interactions between UBE1L-ISG15-UBP43 pathway members may prove important."
22752428
ISG15 binds USP18 and 129-135. 1 / 1
| 1
reach
"In ISG15 bound USP18, residues 129-135 of the thumb domain form an extended loop."
28165509
USP18 binds RSAD2 and ISG15. 1 / 1
| 1
sparser
"IRF7 was the main regulator that changed in both the liver and kidney and was found to interact with other target genes such as USP18, RSAD2, and ISG15."
| PMC
USP18 binds ISG15 and STAT2. 1 / 1
| 1
reach
"The I60N mutation has been shown to disrupt USP18-ISG15-STAT2 protein-protein interactions required for scaffold function in humans.17 50 51 To help clarify the structural basis of these changes, we modeled the USP18-ISG15-STAT2 complex with AlphaFold."
38632987
ISG15 activates USP18.
| 22
ISG15 activates USP18. 10 / 20
| 20
reach
"Indeed, individuals lacking ISG15 expressed lower levels of Ubl carboxy-terminal hydrolase 18 (USP18), which was rescued by complementation with either wild-type or a non-conjugatable form of ISG15 (ref."
29769653
reach
"ISG15 was shown to bind to and prevent USP18 degradation mediated by S-phase kinase-associated protein 2 (SKP2)-dependent ubiquitylation ."
29769653
reach
"The U-ISGF3 target genes, Isg15 and Mx1 [31,32,33], and the ISG15-induced Usp18 [34,35] were all significantly upregulated in response to both PARP7 loss or inhibition (Figure 3K–M), and this increase was greater than that observed for the P-ISGF3 target genes."
37509350
reach
"Interestingly, in human cells, ISG15 directly regulates USP18 stability 24."
28165510
reach
"USP18 exerts a negative regulatory effect on type I interferon signalling by competing with JAK1 for IFNAR2 binding, and mutations in USP18 and ISG15, which directly regulates USP18 stability, result in aberrant type I interferon induction in humans ."
| PMC
reach
"Decreasing ISGylation by knockdown of the ISG15 E1 enzyme, Ube1L, in primary USP18(+/+) and USP18(−/−) hepatocytes led to increased MHV-3 replication."
24648452
reach
"Interestingly, Speer et al. have demonstrated that ISG15-mediated USP18 stabilization occurs in humans but not mice, and mice can regulate the IFN response in the absence of ISG15."
35159348
reach
"Moreover, we confirm that ISG15 promotes USP18 accumulation independently of conjugation 8."
30858391
reach
"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)."
30646630
reach
"Moreover, whereas ISG15 co-expression led to a stabilization and increased abundance of exogenously expressed USP18 (Figure 2E, Input panel), it had no effect on USP41 protein levels."
38853827
ISG15 bound to USP18 activates USP18. 2 / 2
| 2
reach
"In humans, binding of ISG15 to USP18 prevents USP18 degradation, amplifying the inhibition of IFN signaling."
37115698
reach
"The binding interaction between free intracellular human ISG15 and USP18 prevents the SKP-2-mediated degradation of USP18."
27887993
ISG15 inhibits USP18.
| 18
ISG15 inhibits USP18. 10 / 17
| 17
reach
"Recently, human ISG15 deficiency was found to cause a decrease in USP18 accumulation and this was hypothesized to cause the loss of negative feedback of type I interferon signaling in these patients leading to auto-inflammation [XREF_BIBR]."
26555296
reach
"By preventing USP18 degradation ISG15 stabilizes the interaction between IFNAR2 and USP18 (FIG."
32492472
reach
"Overexpressed ISG15 can lead to nonspecific conjugation, while in parallel, excess unconjugated ISG15 can suppress IFN-signaling by stabilizing USP18, a known inhibitor of the IFN pathway [57]."
35764457
reach
"We further show that an absence of intracellular ISG15 in the patients ' cells prevents the accumulation of USP18 XREF_BIBR, XREF_BIBR, a potent negative regulator of IFN-alpha and beta signalling, resulting in the enhancement and amplification of IFN-alpha and beta responses."
25307056
reach
"We therefore analysed the impact of ISG15 on SKP2 mediated USP18 degradation."
25307056
reach
"In subsequent studies, engineered repression of USP18/UBP43 (ISG15 deconjugating enzyme) was shown to destabilize PML-RARα, reduce proliferation, and increase apoptosis in acute promyelocytic leukemia and lung cancer cell lines [169,170,171]."
35159348
reach
"Decreasing ISGylation by knockdown of the ISG15 E1 enzyme, Ube1L, in primary USP18(+/+) and USP18(−/−) hepatocytes led to increased MHV-3 replication."
24648452
reach
"ISG15 prevents degradation of IFNAR’s negative regulator USP18, and as a result, type I IFN signaling is strongly enhanced in the absence of ISG15 (119, 120)."
26958928
reach
"On the other hand, ISG15 can attenuate type I IFN signaling via USP18 stabilization."
38932312
reach
"ISG15 is known to promote USP18-mediated inhibition of type I 437 IFN signaling by stabilizing USP18 activity and preventing its proteasomal degradation(Zhang et 438 al., 2015), underscoring the role of ISG15 as a negative regulator of type I IFN responses when 439 co-upregulated with USP18."
| DOI
ISG15 inhibits USP18-I60N. 1 / 1
| 1
reach
"However, this is unlikely since ISG15 abrogates a complex of SKP2 and USP18 I60N, this latter unable to bind ISG15."
30858391
ISG15 decreases the amount of USP18.
| 4
ISG15 decreases the amount of USP18. 3 / 3
| 3
reach
"ISG15 appeared to act in its unconjugated free form, since silencing of UBE1L or of other ISGylation enzymes failed to reduce USP18 levels (XREF_FIG and XREF_FIG) and patients ' cells transduced with wild-type ISG15 or ISG15 (DeltaGG) exhibited attenuated levels of interferon-stimulated-gene transcripts and proteins (XREF_FIG and XREF_FIG)."
25307056
reach
"These data indicate that intracellular free ISG15 downregulates the IFN-alpha and beta response by maintaining levels of the negative-feedback regulator USP18."
25307056
reach
"We found that ISG15 deficiency led to reduced levels of the negative regulator USP18 because of increased proteolysis due, at least in part, to SKP2 mediated ubiquitination, resulting in stronger responses to IFN-alpha and beta and an ensuing amplification of IFN-alpha and beta-induced responses."
25307056
Modified ISG15 decreases the amount of USP18. 1 / 1
| 1
reach
"As expected from the previous study 10, silencing ISG15 expression decreased the protein level of USP18 in IFN-lambda4-transfected cells."
28630501
ISG15 increases the amount of USP18.
| 3
ISG15 increases the amount of USP18. 3 / 3
| 3
reach
"ISG15 silencing decreased the amount of USP18 protein in recombinant IFN-lambda4-treated cells, and the protein level of USP18 was restored not only by transfection of wild type (WT) ISG15 gene but also by transfection of conjugation defective ISG15 AA mutant gene."
28630501
reach
"In humans, free ISG15 promotes sustained expression of USP18, which negatively regulates IFN signaling (Bogunovic et al., 2012; Zhang et al., 2015; Meuwissen et al., 2016; Speer et al., 2016)."
39512937
reach
"Here we studied the role of ISG15-specific ubiquitin-like protease 43 (USP18) in HIV-1 innate immune sensing.HIV-1 infection induces the expression of USP18 in PMA-differentiated THP-1 cells."
| PMC
ISG15 deubiquitinates USP18.
| 2
ISG15 leads to the deubiquitination of USP18. 2 / 2
| 2
reach
"The coexpression of either wild-type ISG15 or ISG15 (DeltaGG) with USP18 and ubiquitin resulted in markedly lower levels of USP18 ubiquitination (XREF_FIG, lanes 9-11 and XREF_FIG) and larger total amounts of USP18.Overall, these data indicate that free intracellular ISG15 antagonizes USP18 ubiquitination and degradation, thereby promoting the stability and function of this protein."
25307056
reach
"The non-covalent interactions of ISG15 and USP18 prevent the ubiquitination of USP18 by S-phase kinase-associated protein two and stabilize the downregulation of the IFN signaling pathway by USP18 (Tokarz et al., 2004; Zhang et al., 2015)."
34901029
USP18 affects ISG15
12 1 1 | 84 140
USP18 binds ISG15.
12 1 | 50 140
ISG15 binds USP18. 10 / 194
12 1 | 47 134
reach
"In humans, binding of ISG15 to USP18 prevents USP18 degradation, amplifying the inhibition of IFN signaling."
37115698
reach
"We hypothesized that differential catalytic activity across species may be related to substrate affinity.53 Although the catalytic site of USP18 is well conserved between mice and humans, ISG15 sequences vary.52 54 To compare interactions between USP18 and ISG15, we performed a competitive inhibition experiment with cross-species enzyme/substrate pairs."
38632987
reach
"The ability of non-fluorescent ISG15 substrate to compete with fluorescent mISG15-Rho110 substrate is a proxy for affinity between non-fluorescent ISG15 and USP18."
38632987
biogrid
No evidence text available
35962463
sparser
"The association of ISG15 with USP18 interrupts the interaction of USP18 with S-phase kinase-associated protein 2 (SKP2), inhibiting the proteasomal degradation of USP18, which is essential for negative feedback regulation of IFN signaling and prevention of autoinflammation xref , xref ."
36319753
sparser
"USP18 also has enzymatic activity in removing the covalently conjugated 15kDa protein, encoded by interferon-stimulated gene 15 ( ISG15 ), from its targets in a process called de-ISGylation. xref Finally, independent of its affinity for ISGylated proteins, USP18 also binds free ISG15, which protects USP18 against proteasomal degradation, thereby enhancing its negative regulatory capacity. xref "
31940699
sparser
"We recently demonstrated that human free intracellular ISG15 binds USP18, a negative regulator of IFN-α/β signalling."
27193971
reach
"However, the noncovalent binding of free intracellular ISG15 with USP18 inhibits SKP2-mediated USP18 degradation [75,77]."
38675828
sparser
"In humans, ISG15 binds to USP18, increasing its stability and leading to a decrease in IFN-α/β signaling."
30428561
sparser
"Furthermore, we demonstrate that there is a species-specific interaction between ISG15 and USP18."
27193971
UBL binds ISG15 and USP18. 3 / 3
| 3
sparser
"The crystal structure of mouse USP18 in complex with mouse ISG15 displayed extensive interaction between the ISG15 C-terminal Ubl domain and the palm and thumb domain of USP18 (Basters et al., xref )."
32039148
sparser
"Structural data demonstrated that only the ISG15 C-terminal but not the N-terminal UBL domain binds USP18."
32039148
sparser
"However, only the C-terminal Ubl domain of ISG15 interacts with USP18 whereas no interaction between the N-terminal Ubl domain and USP18 was detected and the presence of the N-terminal domain of ISG15 is dispensable for the deISGylation activity of USP18."
30126853
USP18 binds ISG15 and Arg151. 1 / 1
| 1
reach
"A structural overlay of unbound USP18 and the USP18 and ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short alpha-helix of unbound USP18 (XREF_FIG)."
28165509
ISG15 binds USP18 and FASLG. 1 / 1
| 1
sparser
"To confirm that the expected complex between ISG15 and UBP43 formed in APL cells, NB4-S1 cell lysates were immunoprecipitated with an anti-HA antibody, before immunoblotting independently with an anti-HA or the anti-UBP43-1 antibody."
20935222
USP18 binds ISG15 and UBA7. 1 / 1
| 1
sparser
"Interactions between UBE1L-ISG15-UBP43 pathway members may prove important."
22752428
ISG15 binds USP18 and 129-135. 1 / 1
| 1
reach
"In ISG15 bound USP18, residues 129-135 of the thumb domain form an extended loop."
28165509
USP18 binds RSAD2 and ISG15. 1 / 1
| 1
sparser
"IRF7 was the main regulator that changed in both the liver and kidney and was found to interact with other target genes such as USP18, RSAD2, and ISG15."
| PMC
USP18 binds ISG15 and STAT2. 1 / 1
| 1
reach
"The I60N mutation has been shown to disrupt USP18-ISG15-STAT2 protein-protein interactions required for scaffold function in humans.17 50 51 To help clarify the structural basis of these changes, we modeled the USP18-ISG15-STAT2 complex with AlphaFold."
38632987
USP18 activates ISG15.
| 15
USP18 activates ISG15. 10 / 15
| 15
reach
"USP18 can increase HBV susceptibility by removing isopeptidase activity of ISG15 and promoting HBV replication by downregulating the I-IFN signal transduction pathway."
28709980
reach
"Other factors involved in, e.g., type I interferon (IFN) signaling regulation are ubiquitin-specific peptidase 18 (USP18) and interferon-stimulated gene 15 (ISG15), whose expression is itself type I/III IFN induced."
37140667
reach
"Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance."
25605921
reach
"In bladder cancer, USP18 augments the removal of ISG15 from PD-L1, enhancing the stability of PD-L1."
38474186
reach
"Our data are consistent with this mechanism, since the blunting of hepatocyte IFN signaling after exposure to inflammatory stimuli is independent of USP18 mediated removal of ISG15 from its target proteins."
27009955
reach
"At later stages, USP18 mediated de-ISGylation releases free ISG15, which in turn stabilizes USP18 and tunes down IFN-alpha and beta signalling and inflammation."
27193971
reach
"Unlike Lb , USP18-mediated ISG15 cleavage leads to ISG15 recycling since USP18 cleaves the isopeptide linkage after the C-terminal GlyGly motif and ISG15 remains competent for reconjugation."
32039148
reach
"In addition, absence of USP18, which cleaves ISG15 from its target protein, prolongs ISG15 mediated ISGylation."
27809302
reach
"However divergent, ISG15 removal is nevertheless exclusively mediated by USP18 in humans, mice, and zebrafish."
28177072
reach
"Other key negative feedback regulators are ubiquitin-specific peptidase 18 (USP18) and interferon stimulated gene 15 (ISG15) (Figure 2)."
36240739
USP18 inhibits ISG15.
| 11
USP18 inhibits ISG15. 10 / 11
| 11
reach
"Inhibiting USP18, the negative regulator of ISGylation, has been shown in both cell line and invivo systems to enhance ISG15 conjugation (Ketscher et al., 2015)."
31820845
reach
"Here, a clear negative feedback loop can be observed, in which Ubiquitin like protein ISG15 (G1P2) induces IFN-gamma expression while Ubl carboxyl-terminal hydrolase 18 (USP18) inhibits G1P2 activity, explaining the observed down-regulation state of IFN-gamma."
29618802
reach
"In contrast, binding this free ISG15, USP18 suppresses JAK-STAT signaling further counteracting IFN signaling.By better understanding the ISG15 pathway, it may be possible to target certain illnesses on a case-by-case basis without the need for general activation of IFN signaling with its hundreds of downstream targets."
35764457
reach
"Immunoprecipitation (IP) assays confirmed that ISG15 directly complexed with PTEN protein and this conjugation was attenuated by engineered overexpression of USP18."
27980214
reach
"Consistently, USP18 was able to efficiently reverse the ISG15 modification from ADAMTS1 in a dose-dependent manner (Fig. 5G)."
37170317
reach
"USP18 activity reduces ISG15 protein conjugation and promotes tumorigenesis if an oncogenic substrate is stabilized by USP18."
28242811
reach
"USP18 is the main ISG15 isopeptidase and can inhibit 593 ISG15-mediated ISGylation and can repress the establishment of an antiviral state (Honke et al., 594 2016; Ketscher et al., 2015)."
| DOI
reach
"In a positive feedback loop, the ISG15 conjugation system is also upregulated by p53 ISGylation to further potentiate p53 transactivity and downregulated by USP18 mediated deISGylation of p53."
33203188
reach
"In particular, replacement of the Ala138 in USP18 by a polar residue in other USPs might block the access of the bulky and hydrophobic Trp121 side chain of ISG15 (XREF_FIG)."
28165509
reach
"As expected, USP18 silencing dramatically decreased USP18 protein and increased the free ISG15 protein compared to the control group (XREF_FIG)."
27227879
USP18 decreases the amount of ISG15.
| 5
USP18 decreases the amount of ISG15. 5 / 5
| 5
reach
"Knockout of USP18 promotes a higher level of ISG15/ISGylation of p53 and c-myc, which led to higher rate of spontaneous leiomyosarcomas [ 69 ]."
36736853
reach
"Here, we provide an acute example of this phenomenon, whereby the early expression of USP18, post-interferon treatment of HCT116 colon cancer cells is sufficient to fully suppress the expression of the ISG15 E1 enzyme, UBA7."
37756534
reach
"As USP18 deconjugates ISGylation and promotes ISG15 secretion, loss of USP18 increases the intracellular level of ISG15."
36736853
reach
"We demonstrated that USP18 deficient cells have increased expression of IFIT1, IFIT2, IFIT3, IFITM1, IFITM2, CXCL9, CXCL10, ISG15, and MX2 after treatment with exogenous IFN‐β."
29437254
reach
"As expected, incubation with purified USP18 decreased ISG15 conjugates and increased levels of free ISG15 [88]."
35159348
USP18 increases the amount of ISG15.
| 3
USP18 increases the amount of ISG15. 2 / 2
| 2
reach
"The overexpression USP18 significantly inhibited the levels of conjugated ISG15 protein and upregulated the expression of free ISG15 protein in IFNT-induced gEECs ( p < 0.05, Fig. 5 A–C)."
36934584
reach
"As USP18 deconjugates ISGylation and promotes ISG15 secretion, loss of USP18 increases the intracellular level of ISG15."
36736853
Methylated USP18 increases the amount of ISG15. 1 / 1
| 1
reach
"Our results indicate that USP18 promoter hypermethylation caused by oxidative stress increases ISG15 expression in keratinocytes and melanocytes along with senescence changes, leading CD8+ T cells to produce IFN-γ, the main pathogenic cytokine in vitiligo."
37625543
USP18 deubiquitinates ISG15.
1 |
USP18 deubiquitinates ISG15. 1 / 1
1 |
ubibrowser
"Prior work implicated the IFN-stimulated gene 15 (<span class="match term1">ISG15</span>) deubiquitinase (DUB) <span class="match term0">USP18</span> as having antineoplastic activity by regulating lung cancer growth and oncoprotein stability"
28242811
DICER1 affects IFIH1, IRF7, ISG15, MAVS, MX1, OASL, RSAD2, and USP18
| 1
IFIH1 binds ISG15, RSAD2, IRF7, MX1, MAVS, DICER1, USP18, and OASL. 1 / 1
| 1
sparser
"DHX58 is further found to interact with IFIH1, ISG15, RSAD2, IRF7, MX1, MAVS, DICER1, USP18 and OASL."
32405168
Arg151 affects USP18
| 1
USP18 binds ISG15 and Arg151. 1 / 1
| 1
reach
"A structural overlay of unbound USP18 and the USP18 and ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short alpha-helix of unbound USP18 (XREF_FIG)."
28165509
129-135 affects USP18
| 1
ISG15 binds USP18 and 129-135. 1 / 1
| 1
reach
"In ISG15 bound USP18, residues 129-135 of the thumb domain form an extended loop."
28165509