ZUP1 Data Analysis

HGNC Gene Name
zinc finger containing ubiquitin peptidase 1
HGNC Gene Symbol
ZUP1
Identifiers
hgnc:21224 NCBIGene:221302 uniprot:Q96AP4
Orthologs
mgi:1919830 rgd:1307672
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for ZUP1
Number of Papers
8 retrieved on 2022-05-22

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with ZUP1using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value

Literature Mining

INDRA was used to automatically assemble known mechanisms related to ZUP1 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
ZUP1 deubiquitinates DDX58. 2 / 2
| 2

reach
USP3 is also a DUB that deubiquitinates K63-polyUb chain of both RIG-I and MDA5 and suppresses IFN-β activation [25].

reach
However, nairoviruses, like arterviruses, encode DUB enzymes that deubiquitinate RIG-I to prevent innate immune signaling activation (van Kasteren et al., 2012), suggesting that during nairovirus infection/replication a PAMP, likely a viral transcription product, is produced that can activate RIG-I.
ZUP1 deubiquitinates NEDD8. 1 / 1
| 1

reach
DUB, deubiquitylating enzyme; NAE, NEDD8-activating enzyme; PPi, inorganic pyrophosphate; SAE, SUMO-activating enzyme.Figure 2: a | In the first step of UBL activation, E1s bind ATP and a cognate UBL and catalyse the formation of a UBL carboxy- terminal acyl adenylate.
ZUP1 deubiquitinates IFIH1. 1 / 1
| 1

reach
USP3 is also a DUB that deubiquitinates K63-polyUb chain of both RIG-I and MDA5 and suppresses IFN-β activation [25].
ZUP1 deubiquitinates SUDS3. 1 / 1
| 1

reach
DUB-3 (also known as USP17) is a cytokine-inducible human DUB that was found to deubiquitinate SDS3 and block proliferation in HeLa cells [93].
ZUP1 leads to the deubiquitination of NFKBIA. 1 / 1
| 1

reach
The DUB-like SseL factor produced by S. Typhimurium inhibits IkBa ubiquitination in response to the TNF-a cytokine, suggesting that SseL acts directly by removing the K48-linked chains of IkBa (Le Negrate et al., 2008) .
ZUP1 deubiquitinates TRAF3. 1 / 1
| 1

reach
DUBA is an OUT domain-containing DUB that deubiquitinates TRAF3 and inhibits TLR3- and RLRs-mediated activation of IRF3 [93].
ZUP1 deubiquitinates FOXO4. 1 / 1
| 1

reach
Notably, USP7 has been identified as the DUB that deubiquitylates FOXO4 and modulates its transcriptional activity in response to oxidative stress [98], making USP7 a prime controller of oxidative stress responses that are frequent hallmarks of tumours and are often associated with the DDR defects [99].
ZUP1 deubiquitinates TP53. 1 / 1
| 1

reach
We also developed a UbV targeting USP10, a second DUB that deubiquitinates p53, and showed that the UbV promoted export of p53 from the nucleus to the cytoplasm (Zhang, Sartori, et al., 2017).
ZUP1 leads to the deubiquitination of IKB. 1 / 1
| 1

reach
The DUB-like SseL factor produced by S. Typhimurium inhibits IkBα ubiquitination in response to the TNF-α cytokine, suggesting that SseL acts directly by removing the K48-linked chains of IkBα (Le Negrate et al., 2008).
ZUP1 deubiquitinates NLRP7. 1 / 1
| 1

reach
Bednash et al.75 showed that the DUB STAMPBP (or AMSH) deubiquitinates NLRP7 rescuing this receptor from progressing to lysosome degradation and making it available for the formation of an active inflammasome.NLRC4 inflammasome activation can also be controlled by ubiquitination, although very little is known about how this occurs.
ZUP1 deubiquitinates diphosphate(4-). 1 / 1
| 1

reach
DUB, deubiquitylating enzyme; NAE, NEDD8-activating enzyme; PPi, inorganic pyrophosphate; SAE, SUMO-activating enzyme.Figure 2: a | In the first step of UBL activation, E1s bind ATP and a cognate UBL and catalyse the formation of a UBL carboxy- terminal acyl adenylate.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
ZUP1 affects Interferon
| 1 22
ZUP1 inhibits Interferon.
| 1 15
| 1 15

reach
For example, viral DUB activity of CCHFV OTU and equine arteritis virus OTU suppresses type I IFN signaling during infection (7–9), whereas the turnip yellow mosaic virus DUB counters Ub-mediated proteasomal degradation of its polymerase (17).

reach
These results therefore suggest that host cells lack the ability to produce type I IFN in response to MHV-A59 infection.Because ubiquitination plays an important role in the RIG-I-mediated IFN induction cascade 20, and because PLpro domain 2 (PLP2) domain of MHV-A59 contains a conserved DUB motif 22, we hypothesized that the DUB activity of PLP2 domain might block the IFNβ response during MHV-A59 infection.

reach
This DUB activity may remove ubiquitin from innate immune signaling factors to suppress the induction of an antiviral state, and indeed was shown to reduce IFN signaling in biochemical experiments using PL2 pro overexpression for several coronaviruses, including SARS-CoV (Matthews et al. 2014a; ) and MERS-CoV Clementz et al. 2010; Bailey-Elkin et al. 2014) .

reach
These results therefore strongly suggested that PLP2 domain that associated with TBK1/IRF3 complex may contribute to the suppressed IFN response via inactivation of TBK1/IRF3 by its DUB activity in MHV-A59 infected cells.Therefore, by tempering the ubiquitination of both TBK1 and IRF3, and subsequent phosphorylation of both, PLP2 would provide a favorable steric conformation for inter-molecular interaction between inactivated TBK1 and IRF3.

reach
1108 npg therefore suggest that host cells lack the ability to produce type I IFN in response to MHV-A59 infection.Because ubiquitination plays an important role in the RIG-I-mediated IFN induction cascade [20] , and because PLpro domain 2 (PLP2) domain of MHV-A59 contains a conserved DUB motif [22] , we hypothesized that the DUB activity of PLP2 domain might block the IFNβ response during MHV-A59 infection.

reach
It is known that PLpro exhibits deubiquitinating (DUB) activity and antagonizes the induction of type-1 interferon (IFN), the interferon-stimulated gene 15 (ISG15) is the most overexpressed gene upon IFN stimulation and it’s involved in marking newly synthesised protein during an antiviral response.

reach
This DUB activity may remove ubiquitin from innate immune signaling factors to suppress the induction of an antiviral state, and indeed was shown to reduce IFN signaling in biochemical experiments using PL2pro overexpression for several coronaviruses, including SARS-CoV (Matthews et al. 2014a; Li et al. 2016) and MERS-CoV (Chen et al. 2007; Clementz et al. 2010; Bailey-Elkin et al. 2014).

reach
We found that the DUBmut virus replicates similarly to the wild-type (WT) virus in cultured cells, but the DUBmut virus activates an IFN response at earlier times compared to the wild-type virus infection in macrophages, consistent with DUB activity negatively regulating the IFN response.

reach
For example, viral DUB activity of CCHFV OTU and equine arteritis virus OTU suppresses type I IFN signaling during infection (7) (8) (9) , whereas the turnip yellow mosaic virus DUB counters Ub-mediated proteasomal degradation of its polymerase (17) .

reach
In addition, PLpro exhibits deubiquitinating (DUB) activity and antagonizes the induction of type-1 interferon (IFN).
ZUP1 activates Interferon.
| 7
| 5

reach
For example, the DUB enzyme cylindromatosis (CYLD) was shown to directly bind RIG-I and mediate the removal of K63-ub and limit IFN induction [45].

reach
Here we characterized the DUB and IFN antagonism activities of the PLP domains of human coronavirus NL63 and severe acute respiratory syndrome (SARS) coronavirus to determine if DUB activity mediates interferon antagonism.

reach
For instance, above-mentioned studies found the distantly related HCoV-NL63 and SARS-CoV to be similar in essential features such as protease-independent, DUB-mediated IFN antagonism, while the MERS-CoV that is much closer related to SARS-CoV only inhibits IFN induction when the protease function is intact (e.g., [34, 37]).

reach
The blocking of induction of IFN by DUB activity was also confirmed for MERS-CoV, but in contrast to SARS-CoV, this inhibition is not independent of PLP’s protease activity [40, 41].

reach
We further 223 investigated the differences in the interferon response generated in response to WT versus 224 DUBmut virus in our companion study (Volk et al., submitted) , which further supports a role for 225 DUB activity in modulating the interferon response in macrophages.The structure-guided approach used to generate the DUBmut virus allowed for substitution.
| DOI
Mutated ZUP1 activates Interferon. 2 / 2
| 2

reach
We engineered a recombinant murine coronavirus to express the DUB mutant and showed that the DUB mutant virus activated an earlier type I interferon response in macrophages and exhibited reduced replication in mice.

reach
We engineered a recombinant murine coronavirus to express the DUB mutant and showed that the DUB mutant virus activated an earlier type I interferon response in macrophages and exhibited reduced pathogenesis in mice.
| DOI
Protease affects ZUP1
| 2 10
Protease deubiquitinates ZUP1.
| 7
Protease deubiquitinates ZUP1. 7 / 7
| 7

reach
Abstract Coronaviruses encode papain-like proteases (PLpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (DUB)/deISGylating activity, which is hypothesized to modify the innate immune response to infection.

reach
Analysis of enzymatic activity and structural studies revealed that SARS-CoV PLpro and HCoV-NL63 PLP2 function as both proteases and deubiquitinating (DUB) enzymes [14], [32]–[35].

reach
One such multifunctional domain is the coronavirus papain-like protease (PLP), which processes the viral replicase polyprotein, has deubiquitinating (DUB) activity, and antagonizes the induction of type I interferon (IFN).

reach
The removal of Ub is catalysed by proteases generically named deubiquitylating (DUB) enzymes, most of which are cysteine proteinases (Nijman et al, 2005; Sulea et al, 2006).

reach
Coronavirus papain-like proteases (PLPs) can act as proteases that process virus-encoded large replicase polyproteins and also as deubiquitinating (DUB) enzymes.

reach
The papain-like protease of avian infectious bronchitis virus has deubiquitinating activity.Coronavirus papain-like proteases (PLPs) can act as proteases that process virus-encoded large replicase polyproteins and also as deubiquitinating (DUB) enzymes.

reach
Analysis of enzymatic activity and structural studies revealed that SARS-CoV PLpro and HCoV-NL63 PLP2 function as both proteases and deubiquitinating (DUB) enzymes [14, [32] [33] [34] [35] .
Protease activates ZUP1.
| 2 3
Protease activates ZUP1. 5 / 5
| 2 3

reach
Further studies are needed to determine if these inhibitors can be developed into clinically useful antiviral agents.Analysis of SARS-CoV papain-like protease led to the surprising discovery that this protease is also a viral deubiquitinating (DUB) enzyme.
| PMC

eidos
These findings lead us to an intriguing alternative hypothesis , that protease inhibitors reduce the levels / activity of the DUBs that target these viral oncoproteins , thereby causing increased ubiquitination of E6 and E7 , and consequently increased degradation .

eidos
Furthermore , addition of a protease inhibitor that blocks both protease and DUB activity [ 52 ] failed to abrogate the PLP inhibition on activation of IRF-3 dependent promoters [ 14 ] .

reach
For the distantly related arterivirus EAV, infection with a mutant lacking a similar papain-like protease-driven DUB activity resulted in an increased innate immune response after infection, indicating that the viral DUB activity indeed has a function in suppression of innate immune response during infection (van Kasteren et al. 2013).

reach
Further studies are needed to determine if these inhibitors can be developed into clinically useful antiviral agents.Analysis of SARS-CoV papain-like protease led to the surprising discovery that this protease is also a viral deubiquitinating (DUB) enzyme.
| PMC
PLP2 affects ZUP1
| 4 4
PLP2 inhibits ZUP1.
| 3 4
PLP2 inhibits ZUP1. 7 / 7
| 3 4

eidos
We found that mutating 42 the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease 43 activity .
| DOI

reach
For example, the mutations D91R and T88R largely blocked the PLP2 activity and E90R partially blocked the DUB activity (Figure 4).

reach
We found that mutating the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease activity.
| DOI

reach
We found that mutating 42 the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease 43 activity.
| DOI

eidos
We found that mutating the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease activity .

reach
We found that mutating the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease activity.

eidos
We found that mutating the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease activity .
| DOI
PLP2 activates ZUP1.
| 1
PLP2 activates ZUP1. 1 / 1
| 1

eidos
This result suggests that this inhibitory effect of PLP2 is partially dependent on its DUB activity .
ZUP1 affects DNA Damage
| 7
ZUP1 inhibits DNA Damage.
| 5
| 5

reach
Scale bar, 10 μm. See also Figure S6.Figure 7: ZUFSP Prevents Spontaneous DNA Damage and Promotes Cellular Survival in Response Exogenous DNA Damage (A) U2-OS cells were transfected with control (siCTRL) or ZUFSP (siZUFSP) siRNAs for 72 hr and then lysed and analyzed by immunoblotting with the indicated antibodies.

reach
ZUFSP Prevents Spontaneous DNA Damage and Promotes Cellular Survival in Response Exogenous DNA Damage (A) U2-OS cells were transfected with control (siCTRL) or ZUFSP (siZUFSP) siRNAs for 72 hr and then lysed and analyzed by immunoblotting with the indicated antibodies.

reach
While WT ZUFSP effectively rescued the DNA damage phenotype in ZUFSP depleted cells, the C360S mutant was unable to, suggesting that the DUB activity of ZUFSP is required to prevent spontaneous DNA damage in cells (XREF_FIG F).

reach
While WT ZUFSP effectively rescued the DNA damage phenotype in ZUFSP depleted cells, the C360S mutant was unable to, suggesting that the DUB activity of ZUFSP is required to prevent spontaneous DNA damage in cells (Figure 7F).

reach
Furthermore, loss of ZUFSP in human cancer cells led to increased endogenous DNA damage in these cells, and we could further show that this endogenous DNA damage originates in S-phase.
ZUP1 activates DNA Damage.
| 2
| 2

reach
While WT ZUFSP effectively rescued the DNA damage phenotype in ZUFSP depleted cells, the C360S mutant was unable to, suggesting that the DUB activity of ZUFSP is required to prevent spontaneous DNA damage in cells (XREF_FIG F).

reach
While WT ZUFSP effectively rescued the DNA damage phenotype in ZUFSP depleted cells, the C360S mutant was unable to, suggesting that the DUB activity of ZUFSP is required to prevent spontaneous DNA damage in cells (Figure 7F).
Ubiquitin affects ZUP1
| 7
Ubiquitin inhibits ZUP1.
| 5
| 5

reach
Slopes of linear portions of fluorescent signal formation were used to determine the velocity of substrate cleavage in the presence and absence of ubiquitin variant CC.4 (CC.4) which has been shown previously to inhibit DUB activity of CCHFV isolated OTU-domain [27].

reach
DUB activity of both full length protein and OTU domain is inhibited by ubiquitin variant CC.4.

reach
(C) Ubiquitin variant CC.4 inhibits DUB activity of both full length protein and OTU domain to a similar extent as illustrated by the 50% inhibitory concentrations (IC50).

reach
This variation is stated to be advantageous where for example; the DUB to be assayed is inhibited by ubiquitin dimmers [85] .

reach
The ubiquitin variant CC.4 binds to the OTU domain with high affinity and inhibits CCHFV DUB activity [27].
Ubiquitin activates ZUP1.
| 2
| 2

reach
For CCHFV, it was recently shown that the stable occupancy of the CCHFV-encoded DUB with a Ub variant, blocking OTU DUB activity, blocked viral infection in addition to enhancing host antiviral responses [205].

reach
New diUb-VME probes were developed containing two ubiquitin moieties conjugated by one of the seven possible linkage types, thereby allowing the determination of DUB’s linkage specificity (Mulder et al. 2014).
ZUP1 affects IFNB1
| 6
ZUP1 inhibits IFNB1.
| 5
ZUP1 inhibits IFNB1. 4 / 4
| 4

reach
We previously found that the DUB activity of MERS-CoV PLpro suppresses IFN-β promoter activity upon activation of cellular innate immune signaling [9].

reach
For example, herpes simplex virus 1 encodes the largest tegument protein, UL36, which acts as a DUB to remove ubiquitin chains from TNF receptor associated factor 3 (TRAF3) and consequently inhibits IFN-β signaling [89•].

reach
These reports collectively indicate that coronaviruses express viral proteins with DUB activity to reduce IFN-β, which contributes to rapid viral growth and thus SARSassociated immunopathology.

reach
Our results comparing various 3C pro mutants suggest that the DUB activity of 3C pro enables it to block induction of the IFN-β promoter and the Fig. 4 .
Mutated ZUP1 inhibits IFNB1. 1 / 1
| 1

reach
This was supported by a study by Bailey-Elkin et al., in which they obtained the crystal structure of PLpro-Ub complex and showed that WT MERS-CoV PLpro, but not the DUB mutant PLpro, suppresses IFN-β promotor activity [33].
ZUP1 activates IFNB1.
| 1
ZUP1 activates IFNB1. 1 / 1
| 1

reach
Cell-based assays showed that UbV.ME.4 efficiently suppressed the DUB-induced activation of IFN-β promoter, thereby providing efficient blockade of viral replication and reducing MERS-CoV progeny titer by ~10,000-fold (W. Zhang, Bailey-Elkin, et al., 2017).
CSH1 affects ZUP1
| 6
CSH1 deubiquitinates ZUP1.
| 4
CSH1 deubiquitinates ZUP1 on proline. 2 / 2
| 2

reach
Like its SARS-CoV counterpart, the MERS-CoV PL pro also has deubiquitinating (DUB) and deISGylating activities in vivo as well as in vitro (Yang et al., 2013; Mielech et al., 2014; Lei et al., 2014; Baez-Santos et al., 2014b) .

reach
In addition, PL pro exhibits deubiquitinating (DUB) activity and antagonizes the induction of type-1 interferon (IFN).
CSH1 deubiquitinates ZUP1. 2 / 2
| 2

reach
It is known that PL pro exhibits deubiquitinating (DUB) activity and antagonizes the induction of type-1 interferon (IFN), the interferon-stimulated gene 15 (ISG15) is the most overexpressed gene upon IFN stimulation and it's involved in marking newly synthesised protein during an antiviral response.

reach
Herbs and natural compounds able to inhibit the PL PRO 's deubiquitinating (DUB) and deISGylating activities would also increase their effectiveness against the CoV 63,48,90 .
CSH1 inhibits ZUP1.
| 2
CSH1 inhibits ZUP1. 2 / 2
| 2

reach
This also resulted in the strongest inhibition by PL pro , providing a maximum window to assess the effects on IFN-␤ promoter inhibition by the PL pro mutants with specifically inactivated DUB activity.

reach
23 In previous work, we determined the crystal structure of MERS-CoV PL pro in complex with ubiquitin, 24 facilitating the design of PL pro mutations that impair DUB activity without affecting viral polyprotein 25 cleavage.
| DOI
ZUP1 affects Ubiquitin
| 2 4
ZUP1 inhibits Ubiquitin.
| 1 2
| 1 1

eidos
In addition , the ubiquitin-proteasome pathway ( UPP ) regulates p53 stability and is modulated by DUBs that can eliminate ubiquitin from p53 .

reach
A20 is an OTU domain DUB that inhibits NF-kB upstream by removing ubiquitin from TRAF6 and RIP1, two signaling molecules of the NF-kB pathway.
ZUP1 inhibits mutated Ubiquitin. 1 / 1
| 1

reach
Mutation of the ubiquitin-interacting residues of EAV PLP2 had no evident effect on protease activity but significantly reduced DUB activity in overexpression studies.
ZUP1 activates Ubiquitin.
| 1 1
| 1 1

reach
Also as expected, CCHFV-OTU is inhibited by specific inhibitors of DUB enzymes corresponding to ubiquitin and ISG15 derivates coupled to aldehyde or vinyl sulfone [15À18].
| PMC

eidos
DUBs activate ubiquitin prior to conjugation , as well as remove it from the ubiquitinated proteins ( 1 ) .
ZUP1 decreases the amount of Ubiquitin.
| 1
ZUP1 decreases the amount of Ubiquitin. 1 / 1
| 1

reach
Similarly, as one of Coronavirus, it was reported that IBV-encoded PLP-TM functions as a DUB enzyme, which significant reduced the levels of ubiquitin (Ub)-, K48-, and K63-conjugated proteins in the early stage of viral infection [32].
Mutation affects ZUP1
| 5
| 5

eidos
Interestingly , this residue ( equivalent of Glu168 in SARS PLpro ) seems to play an important role in Ub1 core recognition , and mutations can cause a significant loss of DUB activity .

eidos
It is interesting to note that Ile83Ala / Leu86Ala mutations targeted the SAF-A / B , Acinus , and PIAS ( SAP ) domain within Lpro [ 235 ] , and while these mutations selectively abrogate DUB activity [ 240 ] and delay nuclear translocation [ 235 ] , they do not appear to target the likely Ub-binding interface of Lpro , which has been demonstrated to be an effective means to inhibit the DUB activity of other vDUBs [ 162 ] , [ 199 ] .

eidos
Mutations that affect the mobility of the loop and prevent the close conformation resulted in a loss of DUB activity while conserving the protease function [ 27 ] .

eidos
In the case of TYMV , these two activities can be uncoupled by mutations that selectively suppress the DUB activity without altering PRO ( Jupin et al ., 2017 ) .

eidos
This mutation , along with others , abrogated DUB activity yet permitted polyprotein cleavage at the nsp2-3 junction , thus providing an ideal system to directly assess whether PLpro DUB activity alone disrupts cellular signaling .
ZUP1 affects pathogenesis
| 5
ZUP1 activates pathogenesis.
| 4
| 4

reach
Collectively, this 173 demonstrates that CoV PL pro 's DUB activity enhances virulence in an animal model and that selective 174 removal of this activity could be a basis for the design of MLV vaccines.
| DOI

reach
In summary, coronaviruses PLPs are multifunctional enzymes with cysteine protease, DUB and deISGylating activities that contribute significantly to infection pathogenesis.

reach
This study provides the first 35 direct evidence that the DUB activity of a coronaviral protease contributes to innate immune evasion 36 and can profoundly enhance virulence in an animal model.
| DOI

reach
In summary, this indicates that the DUB activity of nsp3 is a major contributor to the pathogenesis of coronavirus infections.
ZUP1 inhibits pathogenesis.
| 1
| 1

reach
Pathogenesis and lethality can thus be reduced by removal of the DUB 649 activity, resulting in earlier, better-regulated and therefore likely more effective innate immune 650 response that helps to clear the virus and decreases pathogenicity, despite the initial viral replication 651 being similar to that seen in wt virus infections.
| DOI

reach
To assess whether DUB-negative mutants indeed induce a stronger 374 innate immune response than wt rMERS-CoV, mRNA levels of IFN-β, IFIT2, and viperin in infected 375 cells were measured by real-time RT-qPCR.
| DOI

reach
This strategy is not unique to viruses because the bacterial virulence factor YopJ also functions as a DUB that inhibits TRAFsmediated innate immune response [35] .

reach
Importantly, we have recently been able to show that the DUB activity of EAV PLP2 inhibits the innate immune response in infected cells, via the structure-based design of a viable mutant virus lacking this activity (van Kasteren et al., 2013).
| 2

reach
Overexpression studies revealed that viral protease/DUB activity can modulate or block activation of the innate immune response pathway.

reach
• Coronaviruses and arteriviruses encode papain-like protease domains that process the replicase polyprotein and are required for viral replication• Many viral papain-like proteases are multifunctional and have protease, deubiquitinating and deISGylating activity• Structural and enzymatic studies revealed the multifunctional nature of coronavirus and arterivirus papain-like proteases• Viral DUB and deISGylating activity is proposed to modulate the innate immune response• An arterivirus papain-like protease has been shown to modulate the innate immune response to viral infection (49) .
ZUP1 affects SGCG
| 5
ZUP1 inhibits SGCG.
| 4
ZUP1 inhibits SGCG. 4 / 4
| 4

reach
For example, viral DUB activity of CCHFV OTU and equine arteritis virus OTU suppresses type I IFN signaling during infection (7) (8) (9) , whereas the turnip yellow mosaic virus DUB counters Ub-mediated proteasomal degradation of its polymerase (17) .

reach
One such multifunctional domain is the coronavirus papain-like protease (PLP), which processes the viral replicase polyprotein, has deubiquitinating (DUB) activity, and antagonizes the induction of type I interferon (IFN).

reach
In particular, the DUB and deISGylating activities encoded by nsp3 suppress the induction and signaling of type I interferons.The functional implication of PTMs on many coronavirus proteins has not been fully characterized, and their biological significance requires further investigations combining reverse genetics and suitable in vivo models.

reach
For example, viral DUB activity of CCHFV OTU and equine arteritis virus OTU suppresses type I IFN signaling during infection (7–9), whereas the turnip yellow mosaic virus DUB counters Ub-mediated proteasomal degradation of its polymerase (17).
ZUP1 activates SGCG.
| 1
Mutated ZUP1 activates SGCG. 1 / 1
| 1

reach
We engineered a recombinant murine coronavirus to express the DUB mutant and showed 44 that the DUB mutant virus activated an earlier type I interferon response in macrophages and 45 exhibited reduced pathogenesis in mice.
| DOI
ZUP1 affects NFkappaB
| 1 3
ZUP1 inhibits NFkappaB.
| 3
| 3

reach
A20 is an OTU domain DUB that inhibits NF-kB upstream by removing ubiquitin from TRAF6 and RIP1, two signaling molecules of the NF-kB pathway.

reach
The YopJ DUB inhibits NF-kB and mitogen-activated protein kinase (MAPK) pathways, a function ascribed previously to its somewhat promiscuous deubiquitination of critical cellular proteins, such as TRAF2, TRAF6, and IkB.

reach
Conversely, CYLD, a human DUB that negatively regulates the NF-kB pathway, is specific for K63-based Ub chains.
ZUP1 activates NFkappaB.
| 1
ZUP1 activates NFkappaB. 1 / 1
| 1

eidos
Investigations into 19S proteasome deubiquitinates showed that inhibition of these DUBs prevents the breakdown of IkappaBalpha and leads to the inactivation of NF-kappaB , which suppresses cardiac remodeling ( Hu et al ., 2018 ) .
| 3

eidos
Ubiquitination is reversed by DUBs and disassembles polyubiquitin chains .

eidos
As mentioned above , the DUB do not just reverse ubiquitination , but they also have many diverse functions , such as protein trafficking , apoptosis , chromatin remodeling , DNA damage repair and cell cycle regulation , and are particularly involved in cell signaling related to cancers ( Antao et al. 2020 ) .

eidos
Deubiquitinating enzymes ( DUB ) can reverse ubiquitination by removing ubiquitin from the substrate ( 100 ) .
| 3

reach
Given that loss of ZUFSP in human cancer cells both causes endogenous DNA replication stress and sensitizes cells to further exogenous DNA damage, it will now be important to understand whether, and how, ZUFSP loss synergizes with defects in other DDR pathways.

reach
Given that loss of ZUFSP in human cancer cells both causes endogenous DNA replication stress and sensitizes cells to further exogenous DNA damage, it will now be important to understand whether, and how, ZUFSP loss synergizes with defects in other DDR pathways.Requests for further information or reagents should be directed to the Lead Contact and corresponding author, Yogesh Kulathu (ykulathu@dundee.ac.uk).

reach
Given that loss of ZUFSP in human cancer cells both causes endogenous DNA replication stress and sensitizes cells to further exogenous DNA damage, it will now be important to understand whether, and how, ZUFSP loss synergizes with defects in other DDR pathways.Detailed methods are provided in the online version of this paper and include the following: We thank H. Walden, C. Arkinson, and members of the Kulathu lab for discussions and critical comments on the manuscript.
WDR48 affects ZUP1
| 3
WDR48 activates ZUP1. 3 / 3
| 3

reach
WDR48 stimulates the activity of three DUBs, USP12, USP46 and USP1, a DUB which regulates the Fanconi anemia DNA damage pathway (Cohn et al., 2007, 2009; Faesen et al., 2011).

reach
WDR48 and WDR20 bind the DUBs relatively far from the catalytic cleft and stimulate DUB catalytic activity via allosteric mechanisms (Figure 1; Yin et al., 2015; Dharadhar et al., 2016; Li et al., 2016).

reach
WDR48 stimulates the activity of three DUBs, USP12, USP46 and USP1, a DUB which regulates the Fanconi anemia DNA damage pathway (Cohn et al., 2007 (Cohn et al., , 2009 Faesen et al., 2011) .
Mutagenesis affects ZUP1
| 3
| 3

eidos
Using reporter assays , we found that blocking the DUB activity by mutagenesis did not completely abrogate the ability of USP15 to inhibit the type I IFN signaling pathway ( Fig. 6 ) .

eidos
However , inhibition of DUB activity by mutagenesis means did not completely abrogate the ability of USP25 to block viral activation of the type I IFN signaling pathway .

eidos
Inhibition of DUB activity by mutagenesis did not abrogate interferon antagonism .
| 3
ZUP1 activates viral process.
| 2
| 2

reach
Specifically, PLPs use their DUB activity to interfere with the proteins that mediate the intracellular sensing and signaling of viral infection, therefore leading to a dysregulation of the immune pathways, such as the IRF3 and NF-kB pathways, that in turn, results in a decrease in the antiviral response.

reach
For CCHFV, it was recently shown that the stable occupancy of the CCHFV-encoded DUB with a Ub variant, blocking OTU DUB activity, blocked viral infection in addition to enhancing host antiviral responses [205].
ZUP1 inhibits viral process.
| 1
| 1

reach
Both Ub and ISG15 are important signaling elements of the host innate immune response against viral infection, which can be negatively regulated by viral DUB and deISGylating enzymes (Calistri et al., 2014).
ZUP1 affects Disease
| 1 2
ZUP1 activates Disease. 2 / 2
| 1 1

eidos
The above examples describe pathological conditions that are caused by expression of heterologous DUBs or by mutations of endogenous DUBs , although many other disease states or cellular functions have been shown to be modulated by DUBs .

reach
The same enzyme preparations can be employed to identify novel polymerase and DUB inhibitors.The tick-born Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe human disease with high fatality rates.
Mutated ZUP1 activates Disease. 1 / 1
| 1

reach
There are only a few DUB mutations that are currently known to cause disease, but it is very likely that more will be recognized in the future.
UCHL1 affects ZUP1
| 3
UCHL1 inhibits ZUP1.
| 2
UCHL1 inhibits ZUP1. 2 / 2
| 2

eidos
Thus , the finding in this study that UCHL1 / L3 inhibition is not as efficient in blocking viral replication as general inhibition of proteasome function or knockdown of ubiquitin is likely attributed to incomplete inhibition of DUBs by UCHL1 / L3 inhibitors .

eidos
Thus , it is speculated that DUB inhibition by UCHL1 / L3 inhibitors alone , in the absence of apparent inhibition of protein degradation , is not sufficient enough to block viral replication .
UCHL1 activates ZUP1.
| 1
UCHL1 activates ZUP1. 1 / 1
| 1

eidos
Although UCHL1 is identified as an important DUB , inhibition of UCHL1 alone has been shown to only partially block the activities of DUBs [ 41 ] .
2 |
Valproic acid decreases the amount of ZUP1. 2 / 2
2 |

ctd
No evidence text available

ctd
No evidence text available

eidos
In fibroblasts derived from Leber Hereditary Optic Neuropathy ( LHON ) harboring the m.11778G > A mutation , DUb highly decreases reactive oxygen species ( ROS ) from affected and control cells [ 102 ] .

eidos
Furthermore , DUB inhibition did not increase ROS levels , nor elicit a strong NRF2-mediated antioxidant response ( based on expression of two canonical target genes NQO1 and GCLC ) ( Figures 4B , 4C and S4B ) .
ZUP1 affects ZC3H12A
| 2
ZUP1 activates ZC3H12A. 2 / 2
| 2

reach
Taking our previously foundation together with the report by Liang et al. [21,22], we think that the DUB activation of MCPIP1 plays important role in its negatively regulation of IFN expression pathway, which is similar to A20 [12,[47], [48], [49]].

reach
Taking our previously foundation together with the report by Liang et al. [21, 22] , we think that the DUB activation of MCPIP1 plays important role in its negatively regulation of IFN expression pathway, which is similar to A20 [12,47e49] .
ZUP1 affects STING1
| 1 1
ZUP1 inhibits STING1. 2 / 2
| 1 1

reach
Thus, these results are consistent with a role for viral DUB activity in antagonizing either the assembly or stability of STING dimers.Recent studies have revealed the arsenal of proteins that viruses use to evade and subvert recognition by pattern-recognition receptors (PRRs) or activation of signaling molecules that are designed to respond to infectious agents [45].

eidos
All three DUBs seem to prevent STING from proteasome-dependent degradation through uncoupling K48-linked ubiquitination after DNA virus infection .
ZUP1 affects Protease
| 2
ZUP1 activates Protease. 2 / 2
| 2

reach
In proteases such as those of CoV, the DUB activity may also contribute totheir cellular lifetimes.For reservoir species, an obvious rule or trend was not apparent.

reach
PLpro is thought to antagonize the IFN response through its deubiquitinating enzyme (DUB) activity, which allows the protease to remove ubiquitin from a substrate.
ZUP1 affects Neoplasms
| 1 1
| 1 1

reach
A benign tumor syndrome of hair follicles known as cylindromatosis is caused by the mutation of CYLD, a USPfamily DUB named after the disease it causes.

eidos
Most DUBs will promote the occurrence of tumors , but a small number of DUBs play the opposite role .
ZUP1 affects NFASC
| 2
ZUP1 inhibits NFASC. 2 / 2
| 2

reach
The YopJ DUB inhibits NF‐κB and mitogen‐activated protein kinase (MAPK) pathways, a function ascribed previously to its somewhat promiscuous deubiquitination of critical cellular proteins, such as TRAF2, TRAF6, and IkB.

reach
A second DUB, A20 (also known as tumour necrosis factor‐α‐induced protein 3, TNFAIP3) negatively regulates NF‐κB signalling.
ZUP1 affects MAVS
| 2
ZUP1 inhibits MAVS. 2 / 2
| 2

reach
This enabled us, for the first time, to demonstrate that the DUB activity of MERS-CoV PL pro can suppress the MAVS-mediated induction of IFN-␤ expression.Cells, Antibodies, and Plasmids-HEK293T cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS; Bodinco BV), 100 units/ml penicillin, 100 units/ml streptomycin, and 2 mM L-glutamine (cell culture medium and supplements were obtained from Lonza).

reach
Thisenabled us, for the first time, to demonstrate that the DUB activity of MERS-CoVPLpro can suppress the MAVS-mediated induction of IFN-βexpression.HEK293T cells were cultured in Dulbecco's modified Eagle's medium (DMEM)supplemented with 10% fetal calf serum (FCS; Bodinco BV), 100 units/mlpenicillin, 100 units/ml streptomycin, and 2 mml-glutamine (cell culture medium and supplements were obtainedfrom Lonza).
ZUP1 affects IRF3
| 2
ZUP1 inhibits IRF3. 2 / 2
| 2

reach
By using a mouse-specific strain of group II coronavirus, MHV-A59, we provide evidence here that a DUB activity conserved among coronavirus nsp3 proteins might specifically inhibit IRF3 activation, and thereby is responsible for viral inhibition of cellular type I IFN production.Most mammalian cells including immune and non-immune cells can produce type I IFNs in response to various viral infections.

reach
At last, using a constitutively active phosphor-mimetic IRF3, it was recently shown that the DUB activity of PLPro also inhibited IRF3 at a postactivation step [196].
ZUP1 affects FBXW7
| 2
ZUP1 inhibits FBXW7. 2 / 2
| 2

reach
In this review, we focus on discussing the specific roles of USP28 in cancer pathways, and their potential therapeutic values in cancer treatment.USP28 was the first FBW7-antagonizing DUB in an shRNA screen using c-MYC stability as a readout in human tumor cells16.

reach
Below, we will review the mechanisms accounting for the involvement of USP28 in these pathways (Fig 3, Table 1 ), hence demonstrating its significance as a therapeutic target for cancer treatment.Disrupting physiological homeostasis of ubiquitination process USP28 was the first FBW7-antagonizing DUB in an shRNA screen using c-MYC stability as a readout in human tumor cells 16 .
WDR20 affects ZUP1
| 1 1
WDR20 activates ZUP1. 2 / 2
| 1 1

reach
WDR48 and WDR20 bind the DUBs relatively far from the catalytic cleft and stimulate DUB catalytic activity via allosteric mechanisms (Figure 1; Yin et al., 2015; Dharadhar et al., 2016; Li et al., 2016).

eidos
The DUB can be further activated by WDR20 , which anchors at the base of BL1 but allosterically regulates the conformation of BL2 and the catalytic cleft .
TP53BP1 affects ZUP1
| 2
TP53BP1 activates ZUP1. 2 / 2
| 2

reach
Using cyclin A as a marker for S/G 2 -phase and 53BP1 as a DNA damage marker, we observed that both G 1 - and S/G 2 -phase cells displays increased 53BP1 signal in ZUFSP depleted cells, indicative of increased DNA breaks in both these cell-cycle phases (XREF_FIG D).

reach
Using cyclin A as a marker for S/G2-phase and 53BP1 as a DNA damage marker, we observed that both G1- and S/G2-phase cells displays increased 53BP1 signal in ZUFSP depleted cells, indicative of increased DNA breaks in both these cell-cycle phases (Figure 7D).
Proteasome affects ZUP1
| 2
Proteasome deubiquitinates ZUP1. 2 / 2
| 2

reach
ISG15 conjugation may also help direct modified proteins to the proteasome, because the proteasome-associated deubiquitinating enzyme (DUB), USP14, can recognize ISG15-modified substrates, or it may function to attract components of the ubiquitin conjugation machinery.ISG15 plays a role in resistance to Ebola virus (also VSV and rabies virus) by blocking the activity of Nedd4 via ISGylation (reviewed in Sadler and Williams, 2008).

reach
Proteasomes function under tonic inhibitory conditions, possibly via the ubiquitin chain-trimming function of USP14, a proteasome-associated deubiquitinating enzyme (DUB).
PRDX5 affects ZUP1
| 2
PRDX5 deubiquitinates ZUP1. 2 / 2
| 2

reach
PLP deubiquitinating (DUB) activity has been demonstrated in several CoV species, and acts directly and indirectly on several signal molecules in the IRF-3-dependent IFN induction pathway including retinoic acid inducible gene-I (RIG-I), tumor necrosis factor receptor-associated factor 3 (TRAF3), TANK-binding kinase 1 (TBK1) and STING [30, 31].

reach
One such multifunctional domain is the coronavirus papain-like protease (PLP), which processes the viral replicase polyprotein, has deubiquitinating (DUB) activity, and antagonizes the induction of type I interferon (IFN).
ZUP1 affects ZUP1
| 2
ZUP1 inhibits ZUP1.
| 1
ZUP1 inhibits ZUP1. 1 / 1
| 1

eidos
DUBs that are cysteine proteases harbor a reactive cysteine residue that can be oxidized by reactive oxygen species ( ROS ) , thus attenuating DUB activity .
ZUP1 activates ZUP1.
| 1
ZUP1 activates ZUP1. 1 / 1
| 1

eidos
When the DUB is inhibited by a DUB inhibitor , the upper band disappears or shows a lower band intensity [ 62,63 ] .
ZUP1 affects Proteasome
| 2
ZUP1 inhibits Proteasome.
| 1
| 1

reach
Conversely, MuRF2 ubiquitination could be enhancing a de-ubiquitinase (DUB) that prevents proteasome-mediated degradation by this unidentified E3(s).
ZUP1 activates Proteasome.
| 1
| 1

reach
Interestingly, the CCHFV OTU protease comprises a domain on the viral polymerase, and targeting it with a UbV may not only suppress viral pathogenicity but RNA replication as well, since it has been found that viral OTU DUB activity can suppress proteasome-dependent viral polymerase degradation [43].
ZUP1 affects ISG15
| 2
ZUP1 inhibits ISG15.
| 1
ZUP1 inhibits ISG15. 1 / 1
| 1

reach
vOTU activity was recently demonstrated to be critical for replication of the often-fatal Crimean-Congo hemorrhagic fever virus, with DUB activity suppressing the type I interferon responses and deISGylase activity broadly removing ISG15 conjugated proteins.
ZUP1 activates ISG15.
| 1
ZUP1 activates ISG15. 1 / 1
| 1

reach
Also as expected, CCHFV-OTU is inhibited by specific inhibitors of DUB enzymes corresponding to ubiquitin and ISG15 derivates coupled to aldehyde or vinyl sulfone [15À18].
| PMC
USP14 affects ZUP1
| 2
USP14 inhibits ZUP1.
| 1
USP14 inhibits ZUP1. 1 / 1
| 1

reach
In addition, loss of the DUB, USP14, reduced neurotransmitter release and increased surface expression of the GABA R (Jarome et al., 2013).
| PMC
USP14 deubiquitinates ZUP1.
| 1
USP14 deubiquitinates ZUP1. 1 / 1
| 1

reach
Proteasomes function under tonic inhibitory conditions, possibly via the ubiquitin chain-trimming function of USP14, a proteasome-associated deubiquitinating enzyme (DUB).
Interferon affects ZUP1
| 2
Interferon inhibits ZUP1.
| 1
| 1

reach
By utilizing DUB activity of ORF64, MHV68 blocked viral DNA induced, STING-mediated IFN production [19].
Interferon activates ZUP1.
| 1
| 1

reach
Mutating the catalytic residue of USP25 was sufficient to block USP25's effect on IFNβ induction, supporting that IFN-β suppression via USP25 is DUB activity dependent [20] .
Vinclozolin affects ZUP1
1 |
Vinclozolin increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Suramin affects ZUP1
| 1
Suramin inhibits ZUP1. 1 / 1
| 1

eidos
While the mechanism of suramin inhibition is beyond the scope of this study , the IC50 results indicate a possibility that suramin is inhibiting BPLF1 and other DUBs in a nonspecific manner .
Sunitinib affects ZUP1
1 |
Sunitinib increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Succimer affects ZUP1
1 |
Succimer increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Rutin affects ZUP1
| 1
Rutin inhibits ZUP1. 1 / 1
| 1

eidos
GRL-0167 , hypericin , and rutin , in order , inhibited DUB activity in another study [ 80 ] .
Quinolone affects ZUP1
| 1
Quinolone deubiquitinates ZUP1. 1 / 1
| 1

reach
Despite having similar molecular size and functionality, the diterpene quinolone tanshinone derivatives, 1-6, inhibit the SARS-CoV PL pro isomerization slow-binding mode, whereas the abietane type derivative, 7, is active against PL pro through the simple slow-binding mode.PL pro , located within nsp3, cleaves at nsp1/2, nsp2/3 and nsp3/4 boundaries using the consensus motif LXGG, along with a consensus cleavage sequence of cellular deubiquitinating (DUB) enzymes.
| 1

reach
Furthermore, addition of a protease inhibitor that blocks both protease and DUB activity [52] failed to abrogate the PLP inhibition on activation of IRF-3 dependent promoters [14].
Probe affects ZUP1
| 1
Probe inhibits ZUP1. 1 / 1
| 1

eidos
Kinetic analysis of DUB inhibition by Ub probes .
| 1

eidos
Phosphorylation also inhibits certain E2s , E3s and DUBs and modulates the ubiquitylation cycle [ 102 ] .
1 |

ctd
No evidence text available
1 |

ctd
No evidence text available
1 |
Pentachlorophenol increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
1 |
Methylparaben increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Methyl affects ZUP1
| 1
Methyl activates ZUP1. 1 / 1
| 1

reach
Monoubiquitin probes targeting the S1 pocket; internal diubiquitin probes targeting S1-S1 0 pockets; terminal diubiquitin probes targeting S1-S2 pockets; Ub-substrate probes targeting S1-S1 0 pockets.The desired irreversible DUB ABPs were synthesized by chemical ligation of the reactive groups (methyl (E)-4-aminobut-2-enoate et al.) with HA-Ub 1-75 -MESNA and purified by cation exchange chromatography.
| PMC
Methyl methanesulfonate increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Magnetite nanoparticle increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
1 |
Lead diacetate increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Jinfukang affects ZUP1
1 |
Jinfukang decreases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Ionomycin affects ZUP1
1 |
Ionomycin decreases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Inhibitor affects ZUP1
| 1
| 1

eidos
The residual activity observed in lysates treated with 50 muM PR-619 is an indication of incomplete inhibition of DUB activity by the inhibitor , suggesting that higher concentrations of the inhibitor would be needed to further decrease the level of DUB activity until a complete inhibition be potentially reached .
Indometacin affects ZUP1
1 |
Indometacin increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Hypericin affects ZUP1
| 1
| 1

eidos
GRL-0167 , hypericin , and rutin , in order , inhibited DUB activity in another study [ 80 ] .
1 |
Hsa-miR-203a-3p decreases the amount of ZUP1. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
Host affects ZUP1
| 1
Host activates ZUP1. 1 / 1
| 1

eidos
Ub and ISG15 are both involved in signaling pathways recognized by the host which further stimulates the innate and anti-viral response.28 , 38 The DUB and deISGYlating activities assists in evasion of the host-innate immune system .
Gold atom affects ZUP1
1 |
Gold atom decreases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Glycidol affects ZUP1
1 |
Glycidol decreases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Dicrotophos affects ZUP1
1 |
Dicrotophos decreases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
1 |
Dexamethasone increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Decabromodiphenyl ether increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
1 |
Cyclosporin A increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
1 |
Copper(II) sulfate increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Cisplatin affects ZUP1
1 |
Cisplatin decreases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Cell cycle affects ZUP1
| 1
| 1

reach
[57] [58] [59] Our findings rationalize that similar to HCMV, other DUB-encoding viruses may perturb normal cell cycle or apoptotic pathways by inhibiting I-IFN synthesis.
Bisphenol A affects ZUP1
1 |
Bisphenol A increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available

reach
[57] [58] [59] Our findings rationalize that similar to HCMV, other DUB-encoding viruses may perturb normal cell cycle or apoptotic pathways by inhibiting I-IFN synthesis.
Benzo[a]pyrene diol epoxide I decreases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Benzene affects ZUP1
1 |
Benzene increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
Arsenite(1-) affects ZUP1
| 1
| 1

reach
An Arsenite Relay between PSMD14 and AIRAP Enables Revival of Proteasomal DUB Activity.
Aflatoxin B1 affects ZUP1
1 |
Aflatoxin B1 increases the amount of ZUP1. 1 / 1
1 |

ctd
No evidence text available
| 1

eidos
DUB inhibitors further decreases the viral replication when used together with proteasome inhibitors through the additional reduction of recycled free ubiquitin .

reach
In particular, the role of robust DUB activity in promoting viral replication and conferring virulence in CCHFV and SARS-CoV emphasizes the impact of the respective proteases and highlights the emerging importance of understanding their effects when considering potential pathogenicity and therapeutic strategies.With the almost perfectly conserved sequence of Ub, it is not surprising that tick-borne nairoviruses from disparate taxa possess notable DUB activity.

reach
Moreover, USP16 is a potent antagonist of Polycomb-dependent repression of gene expression [192] and was recently shown to be a DUB that enables the de-repression of gene transcription following DSB repair [112].
ZUP1 affects substrate
| 1
| 1

eidos
DUB inhibitors may stimulate the degradation of some substrates by directly inhibiting their deubiquitination , or , as discussed , may block the degradation of a substrate indirectly by promoting the degradation of its E3 .

reach
These results show that PEDV infection suppresses production of IFN-β and provides evidence indicating that the PEDV papain-like protease 2 acts as a viral DUB to interfere with the RIG-I- and STING-mediated signalling pathway.
ZUP1 affects protein
| 1
ZUP1 activates protein. 1 / 1
| 1

eidos
The activity of DUBs restores ubiquitinated proteins back to their original forms thereby reversing the effects caused by ubiquitination .

reach
In addition, loss of the DUB, USP14, reduced neurotransmitter release and increased surface expression of the GABA R (Jarome et al., 2013).
| PMC

eidos
These results suggest that while BSO and DUB inhibition induce lipid peroxides , this does not contribute to the cell death observed .
ZUP1 affects interleukins
| 1
| 1

eidos
We will now discuss DUBs that induce interleukins , which are listed in Table 2 .
| 1

eidos
Although the specificities and functions of various deubiquitinases have not been fully characterized , some DUBs that modulate the immune response have been identified .

reach
In addition, loss of the DUB, USP14, reduced neurotransmitter release and increased surface expression of the GABA R (Jarome et al., 2013).
| PMC

reach
This study provides the first 35 direct evidence that the DUB activity of a coronaviral protease contributes to innate immune evasion 36 and can profoundly enhance virulence in an animal model.
| DOI
ZUP1 affects drug
| 1
ZUP1 activates drug. 1 / 1
| 1

reach
Importantly, this work provides proof of concept that potent and selective DUB inhibitors can be achieved and that structural characterization of chemical leads with their cognate DUB target could accelerate probe and drug discovery programs.Detailed methods are provided in the online version of this paper and include the following: Zhang, X.Y., Varthi, M., Sykes, S.M., Phillips, C., Warzecha, C., Zhu, W., Wyce, A., Thorne, A.W., Berger, S.L., and McMahon, S.B.

reach
OTUB1 has DUB-like activity with an almost exclusive preference for K48-linked poly-Ubiquitin [7, 13] , suggesting that it may have DUB enzyme activity-dependent and independent functions.The Ubiquitin-like protein ISG15 (Interferon stimulated gene 15) resembles a di-Ubiquitin moiety and mediates an antiviral response to certain viruses.
| PMC

reach
In addition, because viral DUBs often negatively regulate host innate immunity, it is expected that inactivation of DUB activity should promote the inflammatory cytokine production as reported by several cases [12,15,16,19,61].
ZUP1 affects cell
| 1
ZUP1 activates cell. 1 / 1
| 1

eidos
The screens performed in this study surveyed a broad spectrum of perturbations to identify factors that render cancer cells dependent on GSH and demonstrated that inhibition of DUBs impedes cells from tolerating depletion of GSH .
ZUP1 affects cell death
| 1
| 1

eidos
Inhibition of GSH synthesis , in combination with DUB inhibition , led to an accumulation of polyubiquitinated proteins , induction of proteotoxic stress , and cell death .
ZUP1 affects angiogenesis
| 1
| 1

eidos
DUb suppresses angiogenesis via the ROS / p53 / BAI1 signaling pathway in vascular endothelial cells [ 105 ] .
ZUP1 affects WDR48
| 1
ZUP1 activates WDR48. 1 / 1
| 1

reach
Structures of non-selective DUB inhibitors.Structures of USP1/UAF1 inhibitors.Structures of a representative Novartis USP2 inhibitor and the cathepsin K inhibitor dutacatib.Structures of early USP7 inhibitors from Hybrigenics.USP7 IC50 4.2 μM USP7 IC 50 8.0 μM USP7 IC 50 0.42 μM USP47 IC 50 4.3 μM USP47 IC 50 8.7 μM USP47 IC 50 1.Structures of USP7 inhibitors from Progenra.Structures of recent USP7 inhibitors.Structures of USP8 inhibitors from Hybrigenics.Structures of a USP8 binder and two inhibitors of non-DUB cysteine proteases which advanced to clinical trials.
| 1

eidos
Viruses can encode proteins with DUBs activity [ 32,44,74,75 ] that can enhance virus replication by both direct and indirect mechanisms .
| 1
| 1

reach
This suggests that the DUB-negative MERS-CoV is less effective in evading innate immunity and that the resulting early and balanced immune response is important for controlling the infection, while the delay in innate immune induction caused by the DUB function during wt virus infection dysregulates the response, causing more severe, immunopathological symptoms (unpublished data)[85].
ZUP1 affects USP8
| 1
ZUP1 activates USP8. 1 / 1
| 1

reach
HBX 90,397, another DUB-specific inhibitor, blocks USP8 activity.
| PMC
ZUP1 affects USP1
| 1
ZUP1 activates USP1. 1 / 1
| 1

reach
Structures of non-selective DUB inhibitors.Structures of USP1/UAF1 inhibitors.Structures of a representative Novartis USP2 inhibitor and the cathepsin K inhibitor dutacatib.Structures of early USP7 inhibitors from Hybrigenics.USP7 IC50 4.2 μM USP7 IC 50 8.0 μM USP7 IC 50 0.42 μM USP47 IC 50 4.3 μM USP47 IC 50 8.7 μM USP47 IC 50 1.Structures of USP7 inhibitors from Progenra.Structures of recent USP7 inhibitors.Structures of USP8 inhibitors from Hybrigenics.Structures of a USP8 binder and two inhibitors of non-DUB cysteine proteases which advanced to clinical trials.
ZUP1 affects UBD
| 1
ZUP1 activates UBD. 1 / 1
| 1

reach
Also, the ZUFSP helical arm (ZHA) domain orient in such a way that it moves closer to the Ub, this orientation enables the formation of a UBD which is very peculiar to ZUFSP.
ZUP1 affects TRAF3
| 1
ZUP1 inhibits TRAF3. 1 / 1