ZNF598 is a cytosolic RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27), the human ortholog of yeast Hel2/RQT1, that initiates ribosome-associated quality control (RQC) by acting as the sensor of ribosome collisions. When a trailing ribosome catches up with a slower or stalled leading ribosome (for example during translation of poly(A) stretches or other problematic sequences), ZNF598 specifically recognizes and binds the resulting collided di-ribosome (disome) via its extensive 40S-40S interface. Using the E2 enzyme UBE2D3, it then monoubiquitinates the 40S ribosomal proteins eS10 (RPS10) and uS3 (RPS3) and adds K63-linked polyubiquitin to uS10 (RPS20). This ubiquitin mark recruits the RQT (ribosome quality control trigger) complex, which dissociates the stalled ribosome into subunits and commits the nascent chain to the downstream RQC degradation machinery. ZNF598 is also an RNA-binding protein and a component of the 4EHP-GYF2 complex (with EIF4E2 and GIGYF2), acting as an adaptor that recruits this translational repressor to defective mRNAs and contributing to translation-coupled mRNA decay; it has additional reported roles as a negative regulator of interferon-stimulated gene expression. ZNF598 acts in the cytosol in association with cytosolic ribosomes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043022 ribosome binding | IBA GO_REF:0000033 | ACCEPT | Summary: ZNF598 binds ribosomes - specifically collided di-ribosomes - to carry out its collision-sensing and ubiquitination activities. Reason: Directly demonstrated (IDA) and phylogenetically conserved; ribosome binding is integral to ZNF598's RQC function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt specifically recognizes and binds collided di-ribosome |
| GO:0072344 rescue of stalled cytosolic ribosome | IBA GO_REF:0000033 | ACCEPT | Summary: As the collision sensor that initiates RQC, ZNF598 is central to resolving stalled ribosomes. Reason: Extensively supported experimentally and conserved; ZNF598 initiates the pathway that rescues stalled ribosomes. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt ZNF598 is activated when ribosomes are stalled within an mRNA |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytosolic localization, consistent with experimental IDA evidence. Reason: Correct compartment; ZNF598 acts in the cytosol on ribosomes. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the core RING E3 ligase activity, consistent with direct experimental evidence and EC 2.3.2.27. Reason: Correct core molecular function; redundant with IDA evidence. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control |
| GO:0072344 rescue of stalled cytosolic ribosome | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of the stalled-ribosome rescue process, consistent with experimental evidence. Reason: Correct; redundant with extensive IDA/IMP evidence. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt ZNF598 is activated when ribosomes are stalled within an mRNA |
| GO:0005515 protein binding | IPI PMID:33053355 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA ... | KEEP AS NON CORE | Summary: Interaction with GIGYF1 (O75420), a partner of the 4EHP-GYF2 translational repressor module. Bare protein binding is uninformative. Reason: Records a real interaction relevant to the 4EHP-GYF2 adapter role, but the generic protein binding term is uninformative; not the core RQC ligase function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Q86UK7; O75420: GIGYF1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex interactome capturing a ZNF598-GIGYF1 interaction. Bare protein binding is uninformative. Reason: Real interaction (GIGYF1, O75420) but uninformative term; not the core function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Q86UK7; O75420: GIGYF1 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: OpenCell interactome capturing a ZNF598-YWHAE (14-3-3 epsilon) interaction. Bare protein binding is uninformative. Reason: Real interaction (YWHAE, P62258) but uninformative term; not the core function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Q86UK7; P62258: YWHAE |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | KEEP AS NON CORE | Summary: 14-3-3 chaperone-network study capturing a ZNF598-YWHAE interaction. Bare protein binding is uninformative. Reason: Real interaction (YWHAE, P62258) but uninformative term; not the core function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Q86UK7; P62258: YWHAE |
| GO:0072344 rescue of stalled cytosolic ribosome | TAS Reactome:R-HSA-9948299 | ACCEPT | Summary: Reactome curation of ZNF598's stalled-ribosome rescue role. Reason: Correct; redundant with extensive experimental evidence. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt ZNF598 is activated when ribosomes are stalled within an mRNA |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: General protein ubiquitination process from the UniPathway mapping; a parent of the specific RQC ubiquitination events ZNF598 catalyzes. Reason: Correct but generic; the specific mono- and K63-ubiquitination of 40S proteins better capture ZNF598's role. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:1990261 pre-mRNA catabolic process | NAS PMID:33053355 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA ... | KEEP AS NON CORE | Summary: As part of the 4EHP-GYF2 module with GIGYF1/2, ZNF598 contributes to translation- coupled mRNA decay. This is the adapter/mRNA-decay aspect, distinct from its core RQC ligase role. Reason: Supported by the 4EHP-GYF2 adapter function but peripheral to the core collision- sensing ubiquitin ligase activity. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-9948301 | ACCEPT | Summary: Reactome curation of ZNF598's ubiquitin-protein transferase activity, a parent of the specific ubiquitin protein ligase activity it enables. Reason: Correct general molecular function; the more specific GO:0061630 captures the core RING E3 ligase activity. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948301 | ACCEPT | Summary: Reactome curation of ZNF598 cytosolic localization. Reason: Correct compartment; redundant with experimental cytosol annotations. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948317 | ACCEPT | Summary: Reactome curation of ZNF598 cytosolic localization. Reason: Correct compartment; redundant with experimental cytosol annotations. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0045947 negative regulation of translational initiation | IDA PMID:28065601 Initiation of Quality Control during Poly(A) Translation Req... | KEEP AS NON CORE | Summary: ZNF598-mediated stalling and 4EHP-GYF2 recruitment repress translation of defective mRNAs. This is a downstream consequence of its collision-sensing/adapter role. Reason: Supported, but it is an outcome of the RQC/4EHP-GYF2 activity rather than ZNF598's direct catalytic core function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs |
| GO:0140517 protein-RNA adaptor activity | IDA PMID:32726578 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective ... | KEEP AS NON CORE | Summary: ZNF598 acts as an adaptor linking the 4EHP-GYF2 translational repressor to mRNAs. This is a genuine secondary molecular function distinct from its ligase activity. Reason: Experimentally supported adapter activity, but secondary to the core collision-sensor ubiquitin ligase role; retained as a real non-core molecular function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs |
| GO:0022626 cytosolic ribosome | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: ZNF598 acts on the cytosolic ribosome, marking collided ribosomes with ubiquitin. Reason: Directly demonstrated; ZNF598 functions while bound to cytosolic (collided) ribosomes. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt specifically recognizes and binds collided di-ribosome |
| GO:0005515 protein binding | IPI PMID:28685749 The E3 ubiquitin ligase and RNA-binding protein ZNF598 orche... | KEEP AS NON CORE | Summary: Interaction with the E2 ubiquitin-conjugating enzyme UBE2D3 (P61077), required for ZNF598's ligase activity. Bare protein binding is uninformative but reflects a functionally important partner. Reason: Real, functionally relevant interaction (UBE2D3 E2) but the generic protein binding term is uninformative; the cognate-E2 relationship is captured by the ligase activity. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt E3 ubiquitin-protein ligase activity is dependent on the E2 ubiquitin- conjugating enzyme UBE2D3 |
| GO:0022626 cytosolic ribosome | IDA PMID:30293783 ZNF598 Is a Quality Control Sensor of Collided Ribosomes. | ACCEPT | Summary: ZNF598 acts on the cytosolic collided di-ribosome. Reason: Directly demonstrated; the minimal unit ZNF598 engages is the cytosolic collided ribosome. Supporting Evidence: PMID:30293783 the minimal unit engaged by ZNF598 is the collided |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:28685749 The E3 ubiquitin ligase and RNA-binding protein ZNF598 orche... | ACCEPT | Summary: Direct evidence that ZNF598 is an E3 ubiquitin ligase that ubiquitinates ribosomal proteins during RQC, using UBE2D3. Reason: Core molecular function; directly demonstrated. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt E3 ubiquitin-protein ligase activity is dependent on the E2 ubiquitin- conjugating enzyme UBE2D3 |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:30293783 ZNF598 Is a Quality Control Sensor of Collided Ribosomes. | ACCEPT | Summary: Direct evidence for ZNF598 E3 ligase activity on collided ribosomes. Reason: Core molecular function; directly demonstrated. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3 |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: Direct characterization of ZNF598 ubiquitination activity on collided ribosomes, including K63 polyubiquitination of uS10. Reason: Core molecular function; directly demonstrated. Supporting Evidence: PMID:36302773 the collided ribosomes are first marked by the Hel2/ZNF598 E3 ubiquitin ligase to recruit the RQT complex for subunit dissociation |
| GO:0070534 protein K63-linked ubiquitination | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: ZNF598 catalyzes K63-linked polyubiquitination of uS10 (RPS20) on collided ribosomes, the signal that recruits the RQT complex. Reason: Core; directly demonstrated K63 polyubiquitination of uS10. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Lys-63'-linked polyubiquitination of RPS20/uS10 |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:28685749 The E3 ubiquitin ligase and RNA-binding protein ZNF598 orche... | ACCEPT | Summary: Direct evidence that ZNF598 initiates RQC to resolve stalled ribosomes. Reason: Core, experimentally supported function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt ZNF598 is activated when ribosomes are stalled within an mRNA |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:30293783 ZNF598 Is a Quality Control Sensor of Collided Ribosomes. | ACCEPT | Summary: ZNF598 senses collisions to trigger rescue of stalled ribosomes. Reason: Core, experimentally supported function. Supporting Evidence: PMID:30293783 the minimal unit engaged by ZNF598 is the collided |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:32579943 The ASC-1 Complex Disassembles Collided Ribosomes. | ACCEPT | Summary: ZNF598 ubiquitination upstream of the ASC-1/RQT complex that disassembles collided ribosomes. Reason: Core, experimentally supported function; ZNF598 marks collided ribosomes for disassembly. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt promotes recruitment of the RQT (ribosome quality control trigger) complex |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:33581075 Live-cell imaging reveals kinetic determinants of quality co... | ACCEPT | Summary: Live-cell imaging of ZNF598-triggered quality control of stalled ribosomes. Reason: Core, experimentally supported function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt ZNF598 is activated when ribosomes are stalled within an mRNA |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: ZNF598 marks collided ribosomes to trigger hRQT-mediated subunit dissociation and rescue. Reason: Core, experimentally supported function. Supporting Evidence: PMID:36302773 the collided ribosomes are first marked by the Hel2/ZNF598 E3 ubiquitin ligase to recruit the RQT complex for subunit dissociation |
| GO:0170011 stalled ribosome sensor activity | IDA PMID:30293783 ZNF598 Is a Quality Control Sensor of Collided Ribosomes. | ACCEPT | Summary: ZNF598 is the sensor that recognizes collided di-ribosomes as the proxy for stalling, the defining upstream molecular activity of the RQC pathway. Reason: Core molecular function; ZNF598 is established as the quality-control sensor of collided ribosomes. Supporting Evidence: PMID:30293783 ZNF598 Is a Quality Control Sensor of Collided Ribosomes |
| GO:0072344 rescue of stalled cytosolic ribosome | IMP PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: Loss-of-function evidence that ZNF598 is required for rescue of stalled ribosomes upstream of the RQT trigger complex. Reason: Core, experimentally supported (IMP) function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt promotes recruitment of the RQT (ribosome quality control trigger) complex |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | IMP PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: ZNF598 is required for ribosome-associated ubiquitin-dependent degradation of stalled translation products. Reason: Core, experimentally supported (IMP) biological process. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt followed by degradation of nascent peptides |
| GO:0005829 cytosol | IDA PMID:28757607 Ubiquitination of stalled ribosome triggers ribosome-associa... | ACCEPT | Summary: Direct evidence for cytosolic localization of ZNF598. Reason: Correct compartment; ZNF598 acts in the cytosol on ribosomes. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005515 protein binding | IPI PMID:28065601 Initiation of Quality Control during Poly(A) Translation Req... | KEEP AS NON CORE | Summary: Interactions captured during the foundational ZNF598 RQC study, including ribosomal protein substrates. Bare protein binding is uninformative. Reason: Real interactions (e.g. ribosomal-protein substrates) but the generic term is uninformative; substrate ubiquitination is captured by the ligase activity. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3 |
| GO:0005515 protein binding | IPI PMID:28132843 ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Qual... | KEEP AS NON CORE | Summary: Interactions captured in the ZNF598/RACK1 RQC study. Bare protein binding is uninformative. Reason: Real interactions but the generic term is uninformative; not the core function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3 |
| GO:0006513 protein monoubiquitination | IDA PMID:28065601 Initiation of Quality Control during Poly(A) Translation Req... | ACCEPT | Summary: ZNF598 monoubiquitinates the 40S protein eS10 (and uS3), the initiating mark of RQC on collided ribosomes. Reason: Core; directly demonstrated monoubiquitination of eS10 as the primary ZNF598 target. Supporting Evidence: PMID:28065601 two sites of mono-ubiquitination on the 40S protein eS10 as the primary ribosomal target of ZNF598 |
| GO:0016567 protein ubiquitination | IMP PMID:28132843 ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Qual... | KEEP AS NON CORE | Summary: Loss-of-function evidence that ZNF598 mediates ubiquitination of ribosomal proteins during RQC; a general parent of the specific mono/K63 events. Reason: Correct but generic; the specific monoubiquitination and K63 polyubiquitination annotations better capture ZNF598's role. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3 |
| GO:0043022 ribosome binding | IDA PMID:28065601 Initiation of Quality Control during Poly(A) Translation Req... | ACCEPT | Summary: Direct evidence that ZNF598 binds the ribosome to carry out RQC ubiquitination. Reason: Core; ribosome binding underlies ZNF598's collision-sensing function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt specifically recognizes and binds collided di-ribosome |
| GO:0043022 ribosome binding | IDA PMID:28132843 ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Qual... | ACCEPT | Summary: Direct evidence that ZNF598 binds ribosomes during RQC. Reason: Core; ribosome binding underlies ZNF598's function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt specifically recognizes and binds collided di-ribosome |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:28065601 Initiation of Quality Control during Poly(A) Translation Req... | ACCEPT | Summary: Direct demonstration of ZNF598 E3 ligase activity initiating RQC during poly(A) translation. Reason: Core molecular function; directly demonstrated. Supporting Evidence: PMID:28065601 the ubiquitin ligase ZNF598 is required for ribosomes to terminally stall during translation of poly(A) sequences |
| GO:0061630 ubiquitin protein ligase activity | IMP PMID:28132843 ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Qual... | ACCEPT | Summary: Loss-of-function evidence supporting ZNF598's E3 ligase activity in RQC. Reason: Core molecular function; supported by IMP and corroborated by IDA. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:28065601 Initiation of Quality Control during Poly(A) Translation Req... | ACCEPT | Summary: ZNF598 initiates RQC to rescue stalled ribosomes. Reason: Core, experimentally supported function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt ZNF598 is activated when ribosomes are stalled within an mRNA |
| GO:0072344 rescue of stalled cytosolic ribosome | IMP PMID:28132843 ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Qual... | ACCEPT | Summary: Loss-of-function evidence for ZNF598's role in rescuing stalled ribosomes. Reason: Core, experimentally supported (IMP) function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt ZNF598 is activated when ribosomes are stalled within an mRNA |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: ZNF598 was captured as an mRNA-binding protein in proteome-wide RNA-interactome studies, consistent with its characterized RNA-binding and adapter activity. Reason: Real RNA-binding property (ZNF598 is an RNA-binding protein) but generic; its core function is collision-sensing ubiquitin ligase activity. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | KEEP AS NON CORE | Summary: ZNF598 captured in the mRNA-bound proteome, consistent with its RNA-binding/adapter activity. Reason: Real RNA-binding property but generic; not the core collision-sensor ligase function. Supporting Evidence: file:human/ZNF598/ZNF598-uniprot.txt Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs |
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Download this section (compressed HTML)Q: Why does human ZNF598 preferentially monoubiquitinate eS10 while the K63 polyubiquitination of uS10 is the signal that recruits the RQT complex - are these sequential or parallel marks?
Q: How is ZNF598's collision-sensor ubiquitin ligase role coordinated with its 4EHP-GYF2 adapter function on the same defective mRNAs?
Experiment: Reconstitute ubiquitination of purified collided di-ribosomes with ZNF598 and UBE2D3 to define the order and dependence of eS10/uS3 monoubiquitination versus uS10 K63 polyubiquitination.
Experiment: Separation-of-function ZNF598 mutants (ligase-dead vs collision-binding-deficient vs 4EHP-GYF2-binding-deficient) tested for RQC, mRNA decay, and ISG regulation to dissect its multiple activities.
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