ZNF598

UniProt ID: Q86UK7
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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

Core Functions

RING-type E3 ubiquitin ligase that, on collided ribosomes, monoubiquitinates the 40S proteins eS10 (RPS10) and uS3 (RPS3) and adds K63-linked polyubiquitin to uS10 (RPS20), using the E2 enzyme UBE2D3, to initiate ribosome-associated quality control.

Molecular Function:
ubiquitin protein ligase activity
Cellular Locations:
cytosolic ribosome
Supporting Evidence:
  • file:human/ZNF598/ZNF598-uniprot.txt
    mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3, and 'Lys-63'-linked polyubiquitination of RPS20/uS10
  • PMID:28065601
    two sites of mono-ubiquitination on the 40S protein eS10 as the primary ribosomal target of ZNF598

Sensor of ribosome collisions that specifically recognizes and binds the collided di-ribosome (disome), using collisions as the proxy for aberrant translation to trigger RQC.

Molecular Function:
stalled ribosome sensor activity
Cellular Locations:
cytosolic ribosome
Supporting Evidence:
  • PMID:30293783
    ZNF598 Is a Quality Control Sensor of Collided Ribosomes
  • file:human/ZNF598/ZNF598-uniprot.txt
    specifically recognizes and binds collided di-ribosome

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:22658674
Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
PMID:28065601
Initiation of Quality Control during Poly(A) Translation Requires Site-Specific Ribosome Ubiquitination.
  • ZNF598 is the ubiquitin ligase required for ribosomes to terminally stall on poly(A) sequences, and it monoubiquitinates the 40S protein eS10 as its primary target, initiating RQC.
PMID:28132843
ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation.
  • ZNF598 (with RACK1) mediates regulatory 40S ribosomal ubiquitylation required for mammalian RQC.
PMID:28685749
The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs.
  • ZNF598 is an E3 ligase and RNA-binding protein that, using the E2 UBE2D3, triggers ubiquitination of ribosomal proteins to initiate RQC on poly(A) segments.
PMID:28757607
Ubiquitination of stalled ribosome triggers ribosome-associated quality control.
  • Establishes (in yeast) that Hel2/RQT1-mediated ubiquitination of uS10 triggers RQC; the orthologous activity in human is ZNF598.
PMID:30293783
ZNF598 Is a Quality Control Sensor of Collided Ribosomes.
  • The minimal unit engaged by ZNF598 is the collided di-ribosome; ZNF598 uses ribosome collisions as the proxy for stalling and ubiquitinates targets at the 40S-40S interface.
PMID:32099016
Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells.
  • ZNF598-mediated ubiquitination recruits the mammalian RQT/trigger complex that drives stalled-ribosome disassembly.
PMID:32579943
The ASC-1 Complex Disassembles Collided Ribosomes.
  • The ASC-1/RQT complex disassembles collided ribosomes downstream of ZNF598 ubiquitination.
PMID:32726578
GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
  • ZNF598 is part of the 4EHP-GYF2 module (with EIF4E2 and GIGYF2) that inhibits translation initiation of defective mRNAs, acting as a protein-RNA adaptor.
PMID:33053355
4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
  • ZNF598 interacts with GIGYF1 within the 4EHP-GYF module that mediates translation- coupled mRNA decay.
PMID:33581075
Live-cell imaging reveals kinetic determinants of quality control triggered by ribosome stalling.
  • Live-cell imaging of ZNF598-triggered RQC defines the kinetics of stalling-induced quality control.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:36302773
A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation.
  • ZNF598 catalyzes K63-linked polyubiquitination of uS10 on collided ribosomes to recruit the hRQT complex for subunit dissociation; in human cells eS10 is preferentially monoubiquitinated.
PMID:36931259
A central chaperone-like role for 14-3-3 proteins in human cells.
Reactome:R-HSA-9948299
Reactome: rescue of stalled ribosome (ZNF598)
Reactome:R-HSA-9948301
Reactome: ZNF598 ubiquitin transferase activity / cytosol
Reactome:R-HSA-9948317
Reactome: ZNF598 cytosol localization
file:human/ZNF598/ZNF598-uniprot.txt
UniProt entry Q86UK7 (ZNF598_HUMAN), E3 ubiquitin-protein ligase ZNF598
  • RING E3 ligase and ribosome collision sensor that binds collided di-ribosomes and monoubiquitinates eS10/uS3 and K63-polyubiquitinates uS10 (with E2 UBE2D3) to recruit the RQT complex and initiate RQC; also a 4EHP-GYF2 adapter and RNA-binding protein; cytosolic.

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(ZNF598-notes.md)

ZNF598 (E3 ubiquitin-protein ligase ZNF598; Hel2 ortholog) notes

UniProt: Q86UK7 (ZNF598_HUMAN). RING-type E3 ligase, EC 2.3.2.27. Human ortholog of yeast Hel2/RQT1.

Core function

ZNF598 is the RING E3 ubiquitin ligase that initiates ribosome-associated quality control (RQC)
by sensing collided ribosomes (disomes). On colliding ribosomes it monoubiquitinates 40S
proteins eS10 (RPS10) and uS3 (RPS3) and K63-polyubiquitinates uS10 (RPS20), which recruits the
RQT/hRQT complex to drive subunit dissociation and downstream nascent-chain degradation.

  • UniProt FUNCTION: "Acts as a ribosome collision sensor: specifically recognizes and binds
    collided di-ribosome ... leading to terminally arrest translation."
  • UniProt FUNCTION: "mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and
    RPS3/uS3, and 'Lys-63'-linked polyubiquitination of RPS20/uS10"
  • PMID:28065601
  • PMID:28065601
  • [PMID:30293783 "the minimal unit engaged by ZNF598 is the collided" di-ribosome]
  • PMID:36302773
  • E3 activity depends on E2 UBE2D3 (PMID:28685749).

Sensor / MF annotations

  • GO:0170011 stalled ribosome sensor activity (IDA PMID:30293783) - CORE; ZNF598 is the collision sensor.
  • GO:0061630 ubiquitin protein ligase activity (IDA, many) - CORE.
  • GO:0043022 ribosome binding (IDA PMID:28065601, PMID:28132843) - core; binds 40S/collided ribosomes.
  • GO:0140517 protein-RNA adaptor activity (IDA PMID:32726578) - adapter recruiting 4EHP-GYF2 to mRNAs.
  • GO:0003723 RNA binding (HDA) - ZNF598 is an RNA-binding protein; mRNA-interactome captures.

BP annotations

  • GO:0072344 rescue of stalled cytosolic ribosome (many IDA/IMP) - CORE.
  • GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process (IMP) - core.
  • GO:0070534 protein K63-linked ubiquitination (IDA PMID:36302773) - core; K63 polyUb of uS10.
  • GO:0006513 protein monoubiquitination (IDA PMID:28065601) - core; monoUb of eS10/uS3.
  • GO:0045947 negative regulation of translational initiation (IDA PMID:28065601) - via 4EHP-GYF2 / stalling.
  • GO:0016567 protein ubiquitination (IMP/IEA) - parent.

4EHP-GYF2 adapter / mRNA decay

  • Component of 4EHP-GYF2 complex (EIF4E2, GIGYF2, ZNF598); recruits translational repressor to
    defective mRNAs. PMID:32726578 GIGYF2 and 4EHP inhibit translation initiation of defective mRNAs.
  • GO:1990261 pre-mRNA catabolic process (NAS PMID:33053355, ComplexPortal) - 4EHP/GIGYF translation-
    coupled mRNA decay. KEEP_AS_NON_CORE (adapter role, peripheral to the RQC ligase core).
  • protein binding IPI: GIGYF1 (O75420, PMID:33053355/33961781), YWHAE/14-3-3 (P62258,
    PMID:35271311/36931259), RACK1/GNB2L1 (P63244? actually P61077=UBE2D3), eS10/RPS10(P46783),
    uS3/RPS3(P23396), RPS20(P60866) - some IPI are the actual ribosomal substrates (informative-ish)
    but the bare term is uninformative -> KEEP_AS_NON_CORE.

Moonlighting

  • Negative regulator of interferon-stimulated genes (ISG) (PMID:29719242, not cached) - independent of RQC.
  • Poxvirus protein synthesis (microbial infection). Minor.

Localization

  • Cytoplasm, cytosol; active on cytosolic ribosomes. ACCEPT cytosol/cytosolic ribosome.

Actions summary

  • Core MFs: GO:0170011 stalled ribosome sensor activity; GO:0061630 ubiquitin protein ligase activity.
  • Core BPs: GO:0072344 rescue of stalled ribosome; GO:1990116 RQC catabolism; GO:0070534 K63 ubiquitination;
    GO:0006513 monoubiquitination.
  • ribosome binding, RNA binding, protein-RNA adaptor -> ACCEPT/KEEP_AS_NON_CORE.
  • 4EHP-GYF2 / pre-mRNA catabolic / neg reg translation initiation -> KEEP_AS_NON_CORE (adapter moonlighting).
  • protein binding IPI -> KEEP_AS_NON_CORE.

Pn Notes

(ZNF598-pn-notes.md)

ZNF598 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q86UK7
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 31; KEEP_AS_NON_CORE: 14

PN Consistency Summary

  • Consistency: Fully consistent and exemplary. Notes, review, and PN agree ZNF598 is the RING E3 (Hel2 ortholog) that senses ribosome collisions and ubiquitinates 40S eS10/RPS10, uS3/RPS3 (mono) and uS10/RPS20 (K63) via UBE2D3 to initiate RQC. Review captures this richly: GO:0061630 (IDA), GO:0170011 stalled ribosome sensor activity (IDA), GO:0072344 (many IDA/IMP), GO:1990116, GO:0070534, GO:0006513, GO:0043022. The two PN-projected MF/process targets (GO:0072344, GO:0061630) are both already_in_goa_exact and present in the review.
  • PN story / NEW pressure: PN's RQC-group GO:0006515 (verified real, non-obsolete) is the only new_to_goa projection. The review already captures the RQC process at finer grain via GO:0072344 (rescue) AND GO:1990116 (ribosome-associated ubiquitin-dependent protein catabolic process, verified real) — both more specific than GO:0006515. Conclude: already captured (more specifically); GO:0006515 would be a defensible-but-broader add, not required.
  • Evidence alignment: PN UPS row cites "19489725/rev" (a RING E3 review); RQC TR row has no titled reference. The review's foundational RQC papers (PMID:28065601, 28132843, 28685749, 30293783, 36302773, 32099016) are absent from the PN rows — large divergence, with the review far richer and PN citing only a generic E3 review.
  • Verdict: Consistent and well-captured; ZNF598 is the canonical RQC-initiating E3. PN's GO:0006515 is broader than the review's GO:0072344/GO:1990116; no NEW term needed.

Full Consistency Review

  • UniProt: Q86UK7 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: TR Cytosolic translation|Ribosome-associated QC|Ribosomal rescue; UPS E3 ubiquitin and UBL ligases|RING|other|other ; PN-node mapping: RQC type→GO:0072344 rescue of stalled cytosolic ribosome (mapped, already_in_goa_exact); RQC group→GO:0006515 protein QC for misfolded/incompletely synthesized proteins (new_to_goa); E3 RING group→GO:0061630 ubiquitin protein ligase activity (already_in_goa_exact); class→GO:0061630 (context_only); type/subtype/branch = no_mapping.
  • Consistency: Fully consistent and exemplary. Notes, review, and PN agree ZNF598 is the RING E3 (Hel2 ortholog) that senses ribosome collisions and ubiquitinates 40S eS10/RPS10, uS3/RPS3 (mono) and uS10/RPS20 (K63) via UBE2D3 to initiate RQC. Review captures this richly: GO:0061630 (IDA), GO:0170011 stalled ribosome sensor activity (IDA), GO:0072344 (many IDA/IMP), GO:1990116, GO:0070534, GO:0006513, GO:0043022. The two PN-projected MF/process targets (GO:0072344, GO:0061630) are both already_in_goa_exact and present in the review.
  • PN story / NEW pressure: PN's RQC-group GO:0006515 (verified real, non-obsolete) is the only new_to_goa projection. The review already captures the RQC process at finer grain via GO:0072344 (rescue) AND GO:1990116 (ribosome-associated ubiquitin-dependent protein catabolic process, verified real) — both more specific than GO:0006515. Conclude: already captured (more specifically); GO:0006515 would be a defensible-but-broader add, not required.
  • Mapping strategy: ZNF598 strongly supports both nodes; it does not change the mapping. PN-projected GO:0006515 is broader than the review's GO:0072344/GO:1990116 — a "broader than review" case (cf. TOMM20/HSPA8/RAB7A precedent). E3 RING group→GO:0061630 exact-matches the review core MF. Status/scope correct throughout.
  • Evidence alignment: PN UPS row cites "19489725/rev" (a RING E3 review); RQC TR row has no titled reference. The review's foundational RQC papers (PMID:28065601, 28132843, 28685749, 30293783, 36302773, 32099016) are absent from the PN rows — large divergence, with the review far richer and PN citing only a generic E3 review.
  • Verdict: Consistent and well-captured; ZNF598 is the canonical RQC-initiating E3. PN's GO:0006515 is broader than the review's GO:0072344/GO:1990116; no NEW term needed.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/ZNF598/ZNF598-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | Ribosomal rescue

  • UniProt: Q86UK7
  • In branches: TR, UPS
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal rescue
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0072344 rescue of stalled cytosolic ribosome]
      rationale: This PN RQC type denotes rescue of stalled cytosolic ribosomes. The matching GO process term is the direct target.
    • [group] Translation|Cytosolic translation|Ribosome-associated QC
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
      rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | other | other

  • UniProt: Q86UK7
  • In branches: TR, UPS
  • Signature domains: IPR001841
  • Auxiliary domains: IPR013087
  • PN references (titles):
    • 19489725 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|other|other
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|other
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (3)

  • GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
  • GO:0072344 rescue of stalled cytosolic ribosome | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal rescue
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q86UK7
gene_symbol: ZNF598
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: Q86UK7-1
- name: '2'
  id: Q86UK7-2
  sequence_note: VSP_020661, VSP_020663, VSP_020664
- name: '3'
  id: Q86UK7-3
  sequence_note: VSP_020663
- name: '4'
  id: Q86UK7-4
  sequence_note: VSP_020660, VSP_020662, VSP_020664,
existing_annotations:
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: ZNF598 binds ribosomes - specifically collided di-ribosomes - to carry out its collision-sensing and ubiquitination activities.
    action: ACCEPT
    reason: Directly demonstrated (IDA) and phylogenetically conserved; ribosome binding is integral to ZNF598's RQC function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: specifically recognizes and binds collided di-ribosome
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As the collision sensor that initiates RQC, ZNF598 is central to resolving stalled ribosomes.
    action: ACCEPT
    reason: Extensively supported experimentally and conserved; ZNF598 initiates the pathway that rescues stalled ribosomes.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: ZNF598 is activated when ribosomes are stalled within an mRNA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytosolic localization, consistent with experimental IDA evidence.
    action: ACCEPT
    reason: Correct compartment; ZNF598 acts in the cytosol on ribosomes.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of the core RING E3 ligase activity, consistent with direct experimental evidence and EC 2.3.2.27.
    action: ACCEPT
    reason: Correct core molecular function; redundant with IDA evidence.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of the stalled-ribosome rescue process, consistent with experimental evidence.
    action: ACCEPT
    reason: Correct; redundant with extensive IDA/IMP evidence.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: ZNF598 is activated when ribosomes are stalled within an mRNA
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33053355
  qualifier: enables
  review:
    summary: Interaction with GIGYF1 (O75420), a partner of the 4EHP-GYF2 translational repressor module. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'Q86UK7; O75420: GIGYF1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex interactome capturing a ZNF598-GIGYF1 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (GIGYF1, O75420) but uninformative term; not the core function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'Q86UK7; O75420: GIGYF1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell interactome capturing a ZNF598-YWHAE (14-3-3 epsilon) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (YWHAE, P62258) but uninformative term; not the core function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'Q86UK7; P62258: YWHAE'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36931259
  qualifier: enables
  review:
    summary: 14-3-3 chaperone-network study capturing a ZNF598-YWHAE interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (YWHAE, P62258) but uninformative term; not the core function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'Q86UK7; P62258: YWHAE'
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948299
  qualifier: involved_in
  review:
    summary: Reactome curation of ZNF598's stalled-ribosome rescue role.
    action: ACCEPT
    reason: Correct; redundant with extensive experimental evidence.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: ZNF598 is activated when ribosomes are stalled within an mRNA
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: General protein ubiquitination process from the UniPathway mapping; a parent of the specific RQC ubiquitination events ZNF598 catalyzes.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific mono- and K63-ubiquitination of 40S proteins better capture ZNF598's role.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:1990261
    label: pre-mRNA catabolic process
  evidence_type: NAS
  original_reference_id: PMID:33053355
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Supported by the 4EHP-GYF2 adapter function but peripheral to the core collision- sensing ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948301
  qualifier: enables
  review:
    summary: Reactome curation of ZNF598's ubiquitin-protein transferase activity, a parent of the specific ubiquitin protein ligase activity it enables.
    action: ACCEPT
    reason: Correct general molecular function; the more specific GO:0061630 captures the core RING E3 ligase activity.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948301
  qualifier: located_in
  review:
    summary: Reactome curation of ZNF598 cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948317
  qualifier: located_in
  review:
    summary: Reactome curation of ZNF598 cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0045947
    label: negative regulation of translational initiation
  evidence_type: IDA
  original_reference_id: PMID:28065601
  qualifier: involved_in
  review:
    summary: ZNF598-mediated stalling and 4EHP-GYF2 recruitment repress translation of defective mRNAs. This is a downstream consequence of its collision-sensing/adapter role.
    action: KEEP_AS_NON_CORE
    reason: Supported, but it is an outcome of the RQC/4EHP-GYF2 activity rather than ZNF598's direct catalytic core function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs
- term:
    id: GO:0140517
    label: protein-RNA adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:32726578
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported adapter activity, but secondary to the core collision-sensor ubiquitin ligase role; retained as a real non-core molecular function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36302773
  qualifier: is_active_in
  review:
    summary: ZNF598 acts on the cytosolic ribosome, marking collided ribosomes with ubiquitin.
    action: ACCEPT
    reason: Directly demonstrated; ZNF598 functions while bound to cytosolic (collided) ribosomes.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: specifically recognizes and binds collided di-ribosome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28685749
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase activity is dependent on the E2 ubiquitin- conjugating enzyme UBE2D3
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:30293783
  qualifier: is_active_in
  review:
    summary: ZNF598 acts on the cytosolic collided di-ribosome.
    action: ACCEPT
    reason: Directly demonstrated; the minimal unit ZNF598 engages is the cytosolic collided ribosome.
    supported_by:
    - reference_id: PMID:30293783
      supporting_text: the minimal unit engaged by ZNF598 is the collided
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:28685749
  qualifier: enables
  review:
    summary: Direct evidence that ZNF598 is an E3 ubiquitin ligase that ubiquitinates ribosomal proteins during RQC, using UBE2D3.
    action: ACCEPT
    reason: Core molecular function; directly demonstrated.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase activity is dependent on the E2 ubiquitin- conjugating enzyme UBE2D3
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:30293783
  qualifier: enables
  review:
    summary: Direct evidence for ZNF598 E3 ligase activity on collided ribosomes.
    action: ACCEPT
    reason: Core molecular function; directly demonstrated.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:36302773
  qualifier: enables
  review:
    summary: Direct characterization of ZNF598 ubiquitination activity on collided ribosomes, including K63 polyubiquitination of uS10.
    action: ACCEPT
    reason: Core molecular function; directly demonstrated.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the collided ribosomes are first marked by the Hel2/ZNF598 E3 ubiquitin ligase to recruit the RQT complex for subunit dissociation
- term:
    id: GO:0070534
    label: protein K63-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:36302773
  qualifier: involved_in
  review:
    summary: ZNF598 catalyzes K63-linked polyubiquitination of uS10 (RPS20) on collided ribosomes, the signal that recruits the RQT complex.
    action: ACCEPT
    reason: Core; directly demonstrated K63 polyubiquitination of uS10.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'Lys-63''-linked polyubiquitination of RPS20/uS10'
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:28685749
  qualifier: involved_in
  review:
    summary: Direct evidence that ZNF598 initiates RQC to resolve stalled ribosomes.
    action: ACCEPT
    reason: Core, experimentally supported function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: ZNF598 is activated when ribosomes are stalled within an mRNA
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:30293783
  qualifier: involved_in
  review:
    summary: ZNF598 senses collisions to trigger rescue of stalled ribosomes.
    action: ACCEPT
    reason: Core, experimentally supported function.
    supported_by:
    - reference_id: PMID:30293783
      supporting_text: the minimal unit engaged by ZNF598 is the collided
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:32579943
  qualifier: involved_in
  review:
    summary: ZNF598 ubiquitination upstream of the ASC-1/RQT complex that disassembles collided ribosomes.
    action: ACCEPT
    reason: Core, experimentally supported function; ZNF598 marks collided ribosomes for disassembly.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: promotes recruitment of the RQT (ribosome quality control trigger) complex
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:33581075
  qualifier: involved_in
  review:
    summary: Live-cell imaging of ZNF598-triggered quality control of stalled ribosomes.
    action: ACCEPT
    reason: Core, experimentally supported function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: ZNF598 is activated when ribosomes are stalled within an mRNA
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36302773
  qualifier: involved_in
  review:
    summary: ZNF598 marks collided ribosomes to trigger hRQT-mediated subunit dissociation and rescue.
    action: ACCEPT
    reason: Core, experimentally supported function.
    supported_by:
    - reference_id: PMID:36302773
      supporting_text: the collided ribosomes are first marked by the Hel2/ZNF598 E3 ubiquitin ligase to recruit the RQT complex for subunit dissociation
- term:
    id: GO:0170011
    label: stalled ribosome sensor activity
  evidence_type: IDA
  original_reference_id: PMID:30293783
  qualifier: enables
  review:
    summary: ZNF598 is the sensor that recognizes collided di-ribosomes as the proxy for stalling, the defining upstream molecular activity of the RQC pathway.
    action: ACCEPT
    reason: Core molecular function; ZNF598 is established as the quality-control sensor of collided ribosomes.
    supported_by:
    - reference_id: PMID:30293783
      supporting_text: ZNF598 Is a Quality Control Sensor of Collided Ribosomes
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IMP
  original_reference_id: PMID:32099016
  qualifier: involved_in
  review:
    summary: Loss-of-function evidence that ZNF598 is required for rescue of stalled ribosomes upstream of the RQT trigger complex.
    action: ACCEPT
    reason: Core, experimentally supported (IMP) function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: promotes recruitment of the RQT (ribosome quality control trigger) complex
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:32099016
  qualifier: involved_in
  review:
    summary: ZNF598 is required for ribosome-associated ubiquitin-dependent degradation of stalled translation products.
    action: ACCEPT
    reason: Core, experimentally supported (IMP) biological process.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: followed by degradation of nascent peptides
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:28757607
  qualifier: located_in
  review:
    summary: Direct evidence for cytosolic localization of ZNF598.
    action: ACCEPT
    reason: Correct compartment; ZNF598 acts in the cytosol on ribosomes.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28065601
  qualifier: enables
  review:
    summary: Interactions captured during the foundational ZNF598 RQC study, including ribosomal protein substrates. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions (e.g. ribosomal-protein substrates) but the generic term is uninformative; substrate ubiquitination is captured by the ligase activity.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28132843
  qualifier: enables
  review:
    summary: Interactions captured in the ZNF598/RACK1 RQC study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but the generic term is uninformative; not the core function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:28065601
  qualifier: involved_in
  review:
    summary: ZNF598 monoubiquitinates the 40S protein eS10 (and uS3), the initiating mark of RQC on collided ribosomes.
    action: ACCEPT
    reason: Core; directly demonstrated monoubiquitination of eS10 as the primary ZNF598 target.
    supported_by:
    - reference_id: PMID:28065601
      supporting_text: two sites of mono-ubiquitination on the 40S protein eS10 as the primary ribosomal target of ZNF598
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IMP
  original_reference_id: PMID:28132843
  qualifier: involved_in
  review:
    summary: Loss-of-function evidence that ZNF598 mediates ubiquitination of ribosomal proteins during RQC; a general parent of the specific mono/K63 events.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific monoubiquitination and K63 polyubiquitination annotations better capture ZNF598's role.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IDA
  original_reference_id: PMID:28065601
  qualifier: enables
  review:
    summary: Direct evidence that ZNF598 binds the ribosome to carry out RQC ubiquitination.
    action: ACCEPT
    reason: Core; ribosome binding underlies ZNF598's collision-sensing function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: specifically recognizes and binds collided di-ribosome
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IDA
  original_reference_id: PMID:28132843
  qualifier: enables
  review:
    summary: Direct evidence that ZNF598 binds ribosomes during RQC.
    action: ACCEPT
    reason: Core; ribosome binding underlies ZNF598's function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: specifically recognizes and binds collided di-ribosome
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:28065601
  qualifier: enables
  review:
    summary: Direct demonstration of ZNF598 E3 ligase activity initiating RQC during poly(A) translation.
    action: ACCEPT
    reason: Core molecular function; directly demonstrated.
    supported_by:
    - reference_id: PMID:28065601
      supporting_text: the ubiquitin ligase ZNF598 is required for ribosomes to terminally stall during translation of poly(A) sequences
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:28132843
  qualifier: enables
  review:
    summary: Loss-of-function evidence supporting ZNF598's E3 ligase activity in RQC.
    action: ACCEPT
    reason: Core molecular function; supported by IMP and corroborated by IDA.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:28065601
  qualifier: involved_in
  review:
    summary: ZNF598 initiates RQC to rescue stalled ribosomes.
    action: ACCEPT
    reason: Core, experimentally supported function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: ZNF598 is activated when ribosomes are stalled within an mRNA
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IMP
  original_reference_id: PMID:28132843
  qualifier: involved_in
  review:
    summary: Loss-of-function evidence for ZNF598's role in rescuing stalled ribosomes.
    action: ACCEPT
    reason: Core, experimentally supported (IMP) function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: ZNF598 is activated when ribosomes are stalled within an mRNA
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: ZNF598 was captured as an mRNA-binding protein in proteome-wide RNA-interactome studies, consistent with its characterized RNA-binding and adapter activity.
    action: KEEP_AS_NON_CORE
    reason: Real RNA-binding property (ZNF598 is an RNA-binding protein) but generic; its core function is collision-sensing ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: ZNF598 captured in the mRNA-bound proteome, consistent with its RNA-binding/adapter activity.
    action: KEEP_AS_NON_CORE
    reason: Real RNA-binding property but generic; not the core collision-sensor ligase function.
    supported_by:
    - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
      supporting_text: Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: mRNA-interactome atlas; source of an HDA RNA binding annotation.
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: mRNA-bound proteome study; source of an HDA RNA binding annotation.
- id: PMID:28065601
  title: Initiation of Quality Control during Poly(A) Translation Requires Site-Specific Ribosome Ubiquitination.
  findings:
  - statement: ZNF598 is the ubiquitin ligase required for ribosomes to terminally stall on poly(A) sequences, and it monoubiquitinates the 40S protein eS10 as its primary target, initiating RQC.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational study identifying ZNF598 as the RQC-initiating ribosomal ubiquitin ligase and eS10 as its target.
- id: PMID:28132843
  title: ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation.
  findings:
  - statement: ZNF598 (with RACK1) mediates regulatory 40S ribosomal ubiquitylation required for mammalian RQC.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Independent confirmation of ZNF598-mediated 40S ubiquitylation in RQC.
- id: PMID:28685749
  title: The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs.
  findings:
  - statement: ZNF598 is an E3 ligase and RNA-binding protein that, using the E2 UBE2D3, triggers ubiquitination of ribosomal proteins to initiate RQC on poly(A) segments.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the ZNF598-UBE2D3 E2-E3 pair and dual ligase/RNA-binding nature.
- id: PMID:28757607
  title: Ubiquitination of stalled ribosome triggers ribosome-associated quality control.
  findings:
  - statement: Establishes (in yeast) that Hel2/RQT1-mediated ubiquitination of uS10 triggers RQC; the orthologous activity in human is ZNF598.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Yeast Hel2 study underpinning the ZNF598 ortholog mechanism; cited for ZNF598 cytosol localization in GOA.
- id: PMID:30293783
  title: ZNF598 Is a Quality Control Sensor of Collided Ribosomes.
  findings:
  - statement: The minimal unit engaged by ZNF598 is the collided di-ribosome; ZNF598 uses ribosome collisions as the proxy for stalling and ubiquitinates targets at the 40S-40S interface.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines ZNF598 as the collision sensor and the structural basis of recognition.
- id: PMID:32099016
  title: Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells.
  findings:
  - statement: ZNF598-mediated ubiquitination recruits the mammalian RQT/trigger complex that drives stalled-ribosome disassembly.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Links ZNF598 ubiquitination to the downstream RQT complex.
- id: PMID:32579943
  title: The ASC-1 Complex Disassembles Collided Ribosomes.
  findings:
  - statement: The ASC-1/RQT complex disassembles collided ribosomes downstream of ZNF598 ubiquitination.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Downstream disassembly step following ZNF598 marking.
- id: PMID:32726578
  title: GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
  findings:
  - statement: ZNF598 is part of the 4EHP-GYF2 module (with EIF4E2 and GIGYF2) that inhibits translation initiation of defective mRNAs, acting as a protein-RNA adaptor.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes the ZNF598/4EHP-GYF2 adapter and translational-repression role.
- id: PMID:33053355
  title: 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay.
  findings:
  - statement: ZNF598 interacts with GIGYF1 within the 4EHP-GYF module that mediates translation- coupled mRNA decay.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the GIGYF1 interaction and the pre-mRNA catabolic process NAS annotation.
- id: PMID:33581075
  title: Live-cell imaging reveals kinetic determinants of quality control triggered by ribosome stalling.
  findings:
  - statement: Live-cell imaging of ZNF598-triggered RQC defines the kinetics of stalling-induced quality control.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Kinetic characterization of ZNF598-triggered RQC.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex interactome; uninformative protein binding annotation (GIGYF1).
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell interactome; uninformative protein binding annotation (YWHAE).
- id: PMID:36302773
  title: A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation.
  findings:
  - statement: ZNF598 catalyzes K63-linked polyubiquitination of uS10 on collided ribosomes to recruit the hRQT complex for subunit dissociation; in human cells eS10 is preferentially monoubiquitinated.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Characterizes ZNF598 ubiquitination chemistry (K63 uS10) and the disome interface.
- id: PMID:36931259
  title: A central chaperone-like role for 14-3-3 proteins in human cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: 14-3-3 interactome study; uninformative protein binding annotation (YWHAE).
- id: Reactome:R-HSA-9948299
  title: 'Reactome: rescue of stalled ribosome (ZNF598)'
  findings: []
- id: Reactome:R-HSA-9948301
  title: 'Reactome: ZNF598 ubiquitin transferase activity / cytosol'
  findings: []
- id: Reactome:R-HSA-9948317
  title: 'Reactome: ZNF598 cytosol localization'
  findings: []
- id: file:human/ZNF598/ZNF598-uniprot.txt
  title: UniProt entry Q86UK7 (ZNF598_HUMAN), E3 ubiquitin-protein ligase ZNF598
  findings:
  - statement: RING E3 ligase and ribosome collision sensor that binds collided di-ribosomes and monoubiquitinates eS10/uS3 and K63-polyubiquitinates uS10 (with E2 UBE2D3) to recruit the RQT complex and initiate RQC; also a 4EHP-GYF2 adapter and RNA-binding protein; cytosolic.
    reference_section_type: OTHER
core_functions:
- description: RING-type E3 ubiquitin ligase that, on collided ribosomes, monoubiquitinates the 40S proteins eS10 (RPS10) and uS3 (RPS3) and adds K63-linked polyubiquitin to uS10 (RPS20), using the E2 enzyme UBE2D3, to initiate ribosome-associated quality control.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
    supporting_text: mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3, and 'Lys-63'-linked polyubiquitination of RPS20/uS10
  - reference_id: PMID:28065601
    supporting_text: two sites of mono-ubiquitination on the 40S protein eS10 as the primary ribosomal target of ZNF598
- description: Sensor of ribosome collisions that specifically recognizes and binds the collided di-ribosome (disome), using collisions as the proxy for aberrant translation to trigger RQC.
  molecular_function:
    id: GO:0170011
    label: stalled ribosome sensor activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: PMID:30293783
    supporting_text: ZNF598 Is a Quality Control Sensor of Collided Ribosomes
  - reference_id: file:human/ZNF598/ZNF598-uniprot.txt
    supporting_text: specifically recognizes and binds collided di-ribosome
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: How is ZNF598's collision-sensor ubiquitin ligase role coordinated with its 4EHP-GYF2 adapter function on the same defective mRNAs?
suggested_experiments:
- description: 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.
- description: 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.