DDRGK1

UniProt ID: Q96HY6
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

DDRGK1 (DDRGK domain-containing protein 1; also called UFBP1, Dashurin) is a single-pass endoplasmic-reticulum membrane protein that is an obligate component of the UFM1 ribosome E3 ligase (UREL) complex, together with the E3 ligase UFL1 and CDK5RAP3. DDRGK1 tethers the complex to the ER membrane through its N-terminal transmembrane helix, thereby restricting ufmylation activity to ER-docked ribosomes, and stabilizes UFL1. Following mono-ufmylation of the 60S ribosomal protein RPL26/uL24, DDRGK1 acts as a UFM1 reader, in that its UFM1-interacting motif (UFIM) binds ufmylated RPL26, producing stable association of the 60S subunit with the UREL complex and promoting release and recycling of the large subunit from SEC61 translocons. DDRGK1 is itself a substrate of ufmylation (at Lys-267). Through ER-resident ufmylation it participates in ribosome recycling, reticulophagy (ER-phagy), the response to ER stress and the unfolded protein response (regulating IRE1-alpha/ERN1 stability). Biallelic loss-of-function variants cause Shohat-type spondyloepimetaphyseal dysplasia, reflecting a role in cartilage development via SOX9 stabilization.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0044389 ubiquitin-like protein ligase binding
IBA
GO_REF:0000033 		ACCEPT
Summary: DDRGK1 binds the UFM1 E3 ligase UFL1 directly via its C-terminal region, forming the core of the UREL complex. This binding is central to DDRGK1's adaptor function.
Reason: Direct, experimentally documented binding to the E3 ligase UFL1; this ligase-binding/adaptor activity is a core molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Mediates interaction with UFL1
GO:0051216 cartilage development
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: DDRGK1 is required for cartilage development; loss-of-function variants cause Shohat-type spondyloepimetaphyseal dysplasia, and DDRGK1 stabilizes SOX9.
Reason: A genuine, disease-supported developmental role, but a downstream physiological outcome rather than DDRGK1's core molecular adaptor/reader function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Plays a role in cartilage development through SOX9
GO:1903895 negative regulation of IRE1-mediated unfolded protein response
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: DDRGK1 regulates ERN1/IRE1-alpha stability in a UFM1-dependent manner, modulating the IRE1 arm of the unfolded protein response.
Reason: A valid downstream signaling role mediated by DDRGK1's adaptor function; non-core relative to the molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
regulating ERN1/IRE1-alpha stability
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: DDRGK1 is a single-pass ER membrane protein; this is its principal site of action where it tethers the UREL complex.
Reason: ER membrane localization is well established experimentally and is essential to restrict ufmylation to ER-docked ribosomes.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex affinity-purification interactions. Bare protein binding is uninformative.
Reason: Records real high-throughput interactions but the term is uninformative; core MF is captured by UFL1 binding and UFM1-reader activity.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781
GO:0005515 protein binding
IPI
PMID:35156780
CFTR interactome mapping using the mammalian membrane two-hy... 		KEEP AS NON CORE
Summary: High-throughput interactome interaction. Bare protein binding is uninformative.
Reason: Real interaction record but uninformative term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:35156780
GO:0005515 protein binding
IPI
PMID:36012204
Differential CFTR-Interactome Proximity Labeling Procedures ... 		KEEP AS NON CORE
Summary: High-throughput interactome interaction. Bare protein binding is uninformative.
Reason: Real interaction record but uninformative term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:36012204
GO:0005515 protein binding
IPI
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		KEEP AS NON CORE
Summary: Interaction reported in the mechanistic UREL-complex study (UFL1/CDK5RAP3 partners). Bare term uninformative but reflects cascade interactions.
Reason: Real cascade interactions; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:37595036
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Multimodal cell-maps interaction. Bare protein binding is uninformative.
Reason: Real interaction record but uninformative term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000107 		ACCEPT
Summary: ER localization, consistent with DDRGK1's role as an ER-membrane-anchored adaptor.
Reason: Correct compartment; agrees with stronger experimental ER-membrane evidence.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0034976 response to endoplasmic reticulum stress
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: DDRGK1 functions in ER-stress-associated ufmylation and reticulophagy.
Reason: Valid pathway context; non-core relative to the molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
involved in reticulophagy in response to endoplasmic reticulum stress
GO:0043066 negative regulation of apoptotic process
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Anti-apoptotic role inferred electronically/by similarity; not directly established for human DDRGK1's core function.
Reason: Plausible downstream effect via ER homeostasis; peripheral and electronically inferred.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0043066 negative regulation of apoptotic process biological_process ECO:0000501 IEA
GO:0051216 cartilage development
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Cartilage development, also captured by IBA and IMP evidence.
Reason: Genuine developmental role; non-core relative to molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Plays a role in cartilage development through SOX9
GO:1900100 positive regulation of plasma cell differentiation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Role in B-cell-to-plasma-cell differentiation via ER expansion and UPR regulation, inferred by similarity.
Reason: Plausible immune-differentiation role by orthology; downstream and non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
promoting differentiation of B-cells into plasma cells
GO:1903895 negative regulation of IRE1-mediated unfolded protein response
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic support for the IRE1-UPR regulatory role also documented experimentally.
Reason: Valid downstream signaling role; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
regulating ERN1/IRE1-alpha stability
GO:1903898 negative regulation of PERK-mediated unfolded protein response
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Regulation of the PERK arm of the UPR, inferred by similarity.
Reason: Plausible UPR-modulating role by orthology; downstream and non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
regulating the unfolded protein response
GO:1905552 positive regulation of protein localization to endoplasmic reticulum
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: DDRGK1 promotes protein localization to the ER, inferred electronically; consistent with its ER-tethering role.
Reason: Plausible but electronically inferred; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:1905552 positive regulation of protein localization to endoplasmic reticulum
GO:0005783 endoplasmic reticulum
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct (HPA) immunofluorescence ER localization.
Reason: IDA-supported ER localization consistent with site of action.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA GO_REF:0000052
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		ACCEPT
Summary: Experimental ER membrane localization from the paper identifying the UFM1 E3 ligase.
Reason: Direct experimental support for the principal compartment.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0043123 positive regulation of canonical NF-kappaB signal transduction
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: DDRGK1 modulates NF-kappaB activity through regulation of NFKBIA/IkappaB-alpha stability.
Reason: A documented signaling role but downstream of and separable from DDRGK1's core UREL-adaptor function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
May play a role in NF-
GO:0071569 protein ufmylation
IDA
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: DDRGK1 is required as a UREL-complex component for protein ufmylation.
Reason: Direct evidence for DDRGK1's role in the ufmylation process.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:1990234 transferase complex
IPI
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: DDRGK1 is part of the UREL transferase complex (with UFL1 and CDK5RAP3).
Reason: DDRGK1 is a bona fide subunit of the UFM1 E3 ligase (transferase) complex.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:1990234 transferase complex cellular_component ECO:0000353 IPI PMID:36121123
GO:0141185 UFM1-modified protein reader activity
IDA
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: DDRGK1 reads ufmylated RPL26/uL24 via its UFM1-interacting motif (UFIM), a defining molecular function of the adaptor.
Reason: Direct evidence for UFM1-modified protein reader activity; this is a core molecular function of DDRGK1.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
DDRGK1 specifically binds to ufmylated RPL26/uL24 via its UFIM motif
GO:0141185 UFM1-modified protein reader activity
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		ACCEPT
Summary: Reader activity for ufmylated substrate via the UFIM, demonstrated in the CYB5R3/ER-phagy study.
Reason: Direct support for the core UFM1-reader molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
GO:0141185 UFM1-modified protein reader activity
IDA
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		ACCEPT
Summary: UFIM-dependent reading of ufmylated RPL26 demonstrated mechanistically.
Reason: Direct support for the core reader molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
GO:0141185 UFM1-modified protein reader activity
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: Cryo-EM of the UREL-60S complex shows DDRGK1 UFIM binding ufmylated RPL26.
Reason: Direct structural support for the core reader molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
GO:0141185 UFM1-modified protein reader activity
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: Structural demonstration of DDRGK1 reading ufmylated RPL26 in the UREL-60S complex.
Reason: Direct structural support for the core reader molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
GO:1900100 positive regulation of plasma cell differentiation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Plasma-cell differentiation role transferred from ortholog by sequence similarity.
Reason: Plausible by orthology; downstream and non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
promoting differentiation of B-cells into plasma cells
GO:1903898 negative regulation of PERK-mediated unfolded protein response
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: PERK-UPR regulation transferred from ortholog by sequence similarity.
Reason: Plausible by orthology; downstream and non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
regulating the unfolded protein response
GO:0071569 protein ufmylation
IDA
PMID:35753586
P4HB UFMylation regulates mitochondrial function and oxidati... 		ACCEPT
Summary: DDRGK1 (UREL component) required for ufmylation of P4HB.
Reason: Direct evidence for the ufmylation process role.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:0071569 protein ufmylation
IDA
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostas... 		ACCEPT
Summary: DDRGK1 (UREL component) required for ufmylation of HRD1/SYVN1.
Reason: Direct evidence for the ufmylation process role.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		ACCEPT
Summary: DDRGK1 acts at the ER membrane within the UREL complex.
Reason: Direct evidence for the site of action.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
DDRGK1 tethers the complex to the endoplasmic reticulum membrane
GO:0045732 positive regulation of protein catabolic process
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		KEEP AS NON CORE
Summary: DDRGK1-mediated ufmylation promotes lysosomal degradation of ufmylated proteins (reticulophagy).
Reason: A downstream consequence of ER ufmylation/reticulophagy; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
thereby promoting lysosomal degradation of ufmylated proteins
GO:0071569 protein ufmylation
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		ACCEPT
Summary: DDRGK1 (UREL component) required for ufmylation of CYB5R3.
Reason: Direct evidence for the ufmylation process role.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:0071569 protein ufmylation
IDA
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		ACCEPT
Summary: DDRGK1 required for RPL26 ufmylation/ribosome-associated quality control.
Reason: Direct evidence for the ufmylation process role.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		KEEP AS NON CORE
Summary: DDRGK1, within UREL, contributes to recycling of stalled/post-termination 60S ribosomes at the ER. GOA cross-references this as rescue of stalled ribosome.
Reason: A genuine role in ribosome recycling/RQC; captured as a downstream process while the core MF is the UFM1-reader/adaptor activity.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
plays a key role in ribosome recycling by mediating mono-ufmylation of the RPL26/uL24 subunit
GO:0140501 positive regulation of reticulophagy
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		KEEP AS NON CORE
Summary: DDRGK1-dependent ufmylation promotes reticulophagy (ER-phagy).
Reason: Valid downstream process; non-core relative to molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
involved in reticulophagy in response to endoplasmic reticulum stress
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: DDRGK1 acts at the ER membrane within the UREL-60S complex.
Reason: Direct structural evidence for the site of action.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
DDRGK1 tethers the complex to the endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: DDRGK1 acts at the ER membrane within the UREL-60S complex.
Reason: Direct structural evidence for the site of action.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
DDRGK1 tethers the complex to the endoplasmic reticulum membrane
GO:0032790 ribosome disassembly
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		KEEP AS NON CORE
Summary: UREL-mediated ufmylation promotes dissociation/release of the 60S subunit from the ER translocon.
Reason: Genuine role in 60S release/recycling; downstream process, non-core relative to the reader/adaptor MF.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
dissociation of the 60S ribosome subunit from the endoplasmic reticulum membrane
GO:0032790 ribosome disassembly
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		KEEP AS NON CORE
Summary: UREL-mediated ufmylation promotes 60S release from the ER translocon.
Reason: Genuine role in 60S release/recycling; downstream process, non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
dissociation of the 60S ribosome subunit from the endoplasmic reticulum membrane
GO:0071569 protein ufmylation
IMP
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylatio... 		ACCEPT
Summary: DDRGK1 is required for ufmylation; RPL26 is the principal target.
Reason: Functional support for DDRGK1's role in ufmylation.
Supporting Evidence:
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation
GO:0071569 protein ufmylation
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: DDRGK1 (UREL component) required for RPL26 ufmylation.
Reason: Direct evidence for the ufmylation process role.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:0071569 protein ufmylation
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: DDRGK1 (UREL component) required for RPL26 ufmylation.
Reason: Direct evidence for the ufmylation process role.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		KEEP AS NON CORE
Summary: DDRGK1, within UREL, contributes to recycling of post-termination/stalled 60S ribosomes at the ER.
Reason: Genuine ribosome-recycling/RQC role; downstream process, non-core relative to the reader/adaptor MF.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
plays a key role in ribosome recycling by mediating mono-ufmylation of the RPL26/uL24 subunit
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		KEEP AS NON CORE
Summary: DDRGK1, within UREL, contributes to release/recycling of stalled 60S ribosomes from the ER translocon.
Reason: Genuine ribosome-recycling/RQC role; downstream process, non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
promoting release and recycling of the large ribosomal subunit
GO:0005515 protein binding
IPI
PMID:28128204
A critical role of DDRGK1 in endoplasmic reticulum homoeosta... 		KEEP AS NON CORE
Summary: Interaction with ERN1/IRE1-alpha (UFM1-dependent). Bare term uninformative but reflects a functionally important interaction.
Reason: Real, mechanistically relevant interaction; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28128204
GO:0005515 protein binding
IPI
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: Interaction with UFL1 from the ER-phagy screen. Bare term uninformative.
Reason: Real cascade interaction; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32160526
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		ACCEPT
Summary: ER membrane localization from the ER-phagy screen.
Reason: Direct evidence for principal compartment.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0031647 regulation of protein stability
IDA
PMID:28128204
A critical role of DDRGK1 in endoplasmic reticulum homoeosta... 		KEEP AS NON CORE
Summary: DDRGK1 regulates ERN1/IRE1-alpha stability in a UFM1-dependent manner.
Reason: Documented regulatory role; downstream of the adaptor function, non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
regulating ERN1/IRE1-alpha stability
GO:0034976 response to endoplasmic reticulum stress
IDA
PMID:28128204
A critical role of DDRGK1 in endoplasmic reticulum homoeosta... 		KEEP AS NON CORE
Summary: DDRGK1 functions in ER homeostasis/UPR via IRE1-alpha.
Reason: Valid pathway context; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
A critical role of DDRGK1 in endoplasmic reticulum homoeostasis
GO:0034976 response to endoplasmic reticulum stress
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: DDRGK1 functions in ER-stress-associated ufmylation/reticulophagy.
Reason: Valid pathway context; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
involved in reticulophagy in response to endoplasmic reticulum stress
GO:0061709 reticulophagy
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: DDRGK1 contributes to reticulophagy driven by ER ufmylation.
Reason: Valid downstream process; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
involved in reticulophagy in response to endoplasmic reticulum stress
GO:0070972 protein localization to endoplasmic reticulum
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: DDRGK1 promotes protein localization to the ER.
Reason: Plausible role consistent with ER-tethering; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0070972 protein localization to endoplasmic reticulum biological_process ECO:0000314 IDA PMID:32160526
GO:0071569 protein ufmylation
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		ACCEPT
Summary: DDRGK1 required for ufmylation in the ER-phagy context.
Reason: Direct evidence for the ufmylation process role.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Component of the UFM1 ribosome E3 ligase (UREL) complex
GO:1903895 negative regulation of IRE1-mediated unfolded protein response
IDA
PMID:28128204
A critical role of DDRGK1 in endoplasmic reticulum homoeosta... 		KEEP AS NON CORE
Summary: DDRGK1 negatively regulates the IRE1 arm of the UPR via control of IRE1-alpha stability.
Reason: Documented signaling role; downstream, non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability
GO:1903895 negative regulation of IRE1-mediated unfolded protein response
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: ER-phagy screen supports negative regulation of the IRE1 UPR arm.
Reason: Documented signaling role; downstream, non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability
GO:0005515 protein binding
IPI
PMID:28263186
Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepim... 		KEEP AS NON CORE
Summary: Interaction with SOX9 (from the SEMDSH/cartilage study). Bare term uninformative but reflects a functionally relevant interaction.
Reason: Real interaction relevant to the cartilage role; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28263186
GO:0032435 negative regulation of proteasomal ubiquitin-dependent protein catabolic process
IMP
PMID:28263186
Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepim... 		KEEP AS NON CORE
Summary: DDRGK1 inhibits ubiquitin-mediated proteasomal degradation of SOX9, stabilizing it.
Reason: Documented effect underlying the cartilage role; downstream, non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator
GO:0051216 cartilage development
IMP
PMID:28263186
Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepim... 		KEEP AS NON CORE
Summary: Loss of DDRGK1 causes SEMDSH; DDRGK1 acts in cartilage development through SOX9.
Reason: Genuine disease-supported developmental role; non-core relative to molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Plays a role in cartilage development through SOX9
GO:0045944 positive regulation of transcription by RNA polymerase II
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: Inferred from DDRGK1's modulation of NF-kappaB-dependent transcription.
Reason: Indirect, downstream transcriptional effect via NF-kappaB signaling; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
May play a role in NF-
GO:1902808 positive regulation of cell cycle G1/S phase transition
IC
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: Inferred (IC) cell-cycle effect downstream of DDRGK1's NF-kappaB/proliferation role.
Reason: Indirect downstream effect; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:1902808 positive regulation of cell cycle G1/S phase transition biological_process ECO:0000305 IC PMID:23675531
GO:0030335 positive regulation of cell migration
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: DDRGK1 promotes cell migration in the NF-kappaB study.
Reason: Downstream cellular phenotype; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0030335 positive regulation of cell migration biological_process ECO:0000315 IMP PMID:23675531
GO:0005515 protein binding
IPI
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: Interaction with NFKBIA/IkappaB-alpha. Bare term uninformative.
Reason: Real interaction relevant to the NF-kappaB role; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:23675531
GO:0005737 cytoplasm
TAS
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: Cytoplasmic localization asserted in the NF-kappaB study; DDRGK1 is an ER-membrane protein with a large cytoplasmic domain.
Reason: Consistent with the cytoplasmic-facing topology, but the principal compartment is the ER membrane.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Cytoplasmic
GO:0008284 positive regulation of cell population proliferation
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: DDRGK1 promotes proliferation in the NF-kappaB study.
Reason: Downstream cellular phenotype; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0008284 positive regulation of cell population proliferation biological_process ECO:0000315 IMP PMID:23675531
GO:0010628 positive regulation of gene expression
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: Gene-expression effects downstream of NF-kappaB modulation.
Reason: Indirect downstream effect; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0010628 positive regulation of gene expression biological_process ECO:0000315 IMP PMID:23675531
GO:0010629 negative regulation of gene expression
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: Gene-expression effects downstream of NF-kappaB modulation.
Reason: Indirect downstream effect; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0010629 negative regulation of gene expression biological_process ECO:0000315 IMP PMID:23675531
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: DDRGK1 promotes NFKBIA proteasomal degradation in the NF-kappaB study.
Reason: Downstream effect within NF-kappaB signaling; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process biological_process ECO:0000315 IMP PMID:23675531
GO:0043066 negative regulation of apoptotic process
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Anti-apoptotic role transferred from ortholog by sequence similarity.
Reason: Plausible by orthology; downstream and non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0043066 negative regulation of apoptotic process biological_process ECO:0000250 ISS GO_REF:0000024
GO:1905552 positive regulation of protein localization to endoplasmic reticulum
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Transferred from ortholog by sequence similarity; consistent with ER-tethering role.
Reason: Plausible by orthology; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:1905552 positive regulation of protein localization to endoplasmic reticulum biological_process ECO:0000250 ISS GO_REF:0000024
GO:1990592 protein K69-linked ufmylation
IDA
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: DDRGK1 participates in UFM1 conjugation, including K69-linked UFM1 chains.
Reason: Specific chain-linkage sub-aspect of ufmylation; narrow process annotation.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:1990592 protein K69-linked ufmylation biological_process ECO:0000314 IDA PMID:25219498
GO:0005515 protein binding
IPI
PMID:20228063
A novel C53/LZAP-interacting protein regulates stability of ... 		KEEP AS NON CORE
Summary: Interaction with CDK5RAP3 (a UREL component). Bare term uninformative but reflects a cascade interaction.
Reason: Real cascade interaction; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20228063
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:20228063
A novel C53/LZAP-interacting protein regulates stability of ... 		ACCEPT
Summary: Experimental ER membrane localization.
Reason: Direct evidence for principal compartment.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0033146 regulation of intracellular estrogen receptor signaling pathway
IDA
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: DDRGK1 contributes to ufmylation of ASC1/TRIP4, affecting ERalpha transactivation.
Reason: A documented but specialized signaling role downstream of ufmylation; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
May also be required for TRIP4 ufmylation
GO:0034976 response to endoplasmic reticulum stress
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ER stress response transferred from ortholog by sequence similarity.
Reason: Valid pathway context by orthology; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
involved in reticulophagy in response to endoplasmic reticulum stress
GO:1901800 positive regulation of proteasomal protein catabolic process
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: DDRGK1 promotes proteasomal catabolism of NFKBIA in the NF-kappaB study.
Reason: Downstream effect within NF-kappaB signaling; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:1901800 positive regulation of proteasomal protein catabolic process biological_process ECO:0000315 IMP PMID:23675531
GO:1903721 positive regulation of I-kappaB phosphorylation
IMP
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalp... 		KEEP AS NON CORE
Summary: DDRGK1 promotes IkappaB-alpha phosphorylation, activating NF-kappaB.
Reason: Downstream signaling effect; non-core.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:1903721 positive regulation of I-kappaB phosphorylation biological_process ECO:0000315 IMP PMID:23675531
GO:0005515 protein binding
IPI
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: Interaction with UFL1/TRIP4 in the ASC1/ufmylation study. Bare term uninformative.
Reason: Real cascade-relevant interaction; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25219498
GO:0044389 ubiquitin-like protein ligase binding
IPI
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		ACCEPT
Summary: Direct interaction with the UFM1 E3 ligase UFL1, the core adaptor binding activity of DDRGK1.
Reason: Direct experimental support for the core UFL1-binding/adaptor molecular function.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
Mediates interaction with UFL1
GO:0005515 protein binding
IPI
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		KEEP AS NON CORE
Summary: Interaction with UFL1 from the paper identifying the UFM1 E3 ligase. Bare term uninformative.
Reason: Real cascade interaction; non-core under generic term.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20018847
GO:0005783 endoplasmic reticulum
IDA
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		ACCEPT
Summary: Experimental ER localization from the UFM1 E3 ligase paper.
Reason: Direct evidence for principal compartment.
Supporting Evidence:
file:human/DDRGK1/DDRGK1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane

Core Functions

Obligate ER-membrane-anchored cofactor/substrate-adaptor of the UFM1 E3 ligase that binds the E3 ligase UFL1 (and CDK5RAP3) to form the UREL complex, tethering ufmylation activity to ER-docked ribosomes and stabilizing UFL1.

Molecular Function:
ubiquitin-like protein ligase binding
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • file:human/DDRGK1/DDRGK1-uniprot.txt
    Mediates interaction with UFL1
  • file:human/DDRGK1/DDRGK1-uniprot.txt
    DDRGK1 tethers the complex to the endoplasmic reticulum membrane

UFM1-modified protein reader that, via its UFM1-interacting motif (UFIM), specifically binds ufmylated RPL26/uL24 on the 60S ribosome, producing stable association of the 60S subunit with the UREL complex and promoting release/recycling of the large subunit from the ER translocon.

Molecular Function:
UFM1-modified protein reader activity
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • file:human/DDRGK1/DDRGK1-uniprot.txt
    The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system.
  • DDRGK1 interacts with the UFM1 E3 ligase UFL1 and is ufmylated at Lys-267; it localizes to the ER.
PMID:20228063
A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling.
  • DDRGK1 interacts with CDK5RAP3/C53 and its stability is co-regulated; it modulates NF-kappaB signaling.
PMID:23675531
DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha stability.
  • DDRGK1 modulates NF-kappaB activity by regulating NFKBIA/IkappaB-alpha stability.
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
  • DDRGK1 interacts with UFL1 and is required for TRIP4/ASC1 ufmylation, affecting ERalpha transactivation.
PMID:28128204
A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1alpha stability.
  • DDRGK1 interacts with ERN1/IRE1-alpha in a UFM1-dependent manner and regulates its stability, inhibiting the IRE1 arm of the UPR.
PMID:28263186
Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia.
  • Loss-of-function DDRGK1 variants cause Shohat-type spondyloepimetaphyseal dysplasia; DDRGK1 stabilizes SOX9 by inhibiting its ubiquitin-mediated degradation.
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation.
  • RPL26 is the principal cellular target of UFMylation.
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-Resident UFMylation.
  • DDRGK1 and ER-resident UFMylation are required for ER-phagy and IRE1 UPR regulation.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35156780
CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system.
PMID:35753586
P4HB UFMylation regulates mitochondrial function and oxidative stress.
PMID:36012204
Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters.
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
  • DDRGK1 is a component of the UREL complex and reads ufmylated RPL26 via its UFIM motif.
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
  • DDRGK1 UFIM reads ufmylated substrate; UREL-dependent ufmylation of CYB5R3 drives ER-phagy.
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control.
  • DDRGK1 UFIM-dependent reading of ufmylated RPL26 stabilizes 60S-UREL association and supports ribosome-associated quality control.
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.
  • Cryo-EM of the UREL-60S complex shows DDRGK1 tethering and UFIM reading of ufmylated RPL26 to promote 60S recycling.
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
  • UREL (UFL1/DDRGK1/CDK5RAP3) ufmylates RPL26 to release/recycle 60S ribosomes from ER translocons; DDRGK1 single-pass membrane anchor and UFIM are key.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.

Suggested Questions for Experts

Q: Is ufmylation of DDRGK1 at Lys-267 functionally required for UREL activity or is it a collateral consequence of the reaction it scaffolds?

Q: How are the ER-stress/UPR (IRE1-alpha), NF-kappaB and SOX9/cartilage roles of DDRGK1 related to its UREL ribosome-recycling function - are they separable activities or downstream consequences of ER ufmylation?

Suggested Experiments

Experiment: Separation-of-function mutants (UFIM-dead vs UFL1-binding-dead vs Lys-267 ufmylation-dead) tested in 60S-recycling, IRE1-alpha-stability and SOX9-stability assays to dissect which DDRGK1 activities drive each phenotype.

Experiment: Reconstitute the UREL-60S complex with purified components to quantify the contribution of DDRGK1 membrane-tethering and UFIM reading to RPL26 ufmylation kinetics and 60S release from SEC61.

πŸ“š Additional Documentation

Notes

(DDRGK1-notes.md)

DDRGK1 / UFBP1 (DDRGK domain-containing protein 1) β€” research notes

UniProt: Q96HY6 (DDRGK_HUMAN), 314 aa. HGNC:16110. Chromosome 20. Synonyms: UFBP1, Dashurin, C20orf116.

Role in the cascade

DDRGK1 is the obligate cofactor / substrate-adaptor of the UFM1 E3 ligase, a component of the
UREL complex (UFL1 + DDRGK1 + CDK5RAP3). It is a single-pass ER membrane protein (TM 1–28;
cytoplasmic 29–314) that tethers UREL to the ER membrane, restricting ufmylation to ER-docked ribosomes,
and stabilizes UFL1.
- UniProt: "Within the UREL complex, DDRGK1 tethers the complex to the endoplasmic reticulum membrane."
- Binds the E3 ligase UFL1 via its C-terminal region (region 216–314) β†’ core MF GO:0044389 ubiquitin-like protein ligase binding.

UFM1 reader

DDRGK1 has a UFM1-interacting motif (UFIM, residues 195–209) that specifically recognizes ufmylated
RPL26/uL24 β†’ core MF GO:0141185 UFM1-modified protein reader activity [PMID:36121123, PMID:36543799,
PMID:37595036, PMID:38383785, PMID:38383789]. Reading ufmylated RPL26 stabilizes the 60S–UREL association
and drives release/recycling of the 60S subunit from the ER translocon.

Substrate / PTM

DDRGK1 is itself ufmylated at Lys-267 by UFL1; whether this is functional or collateral is unclear (UniProt).

Other roles (downstream / non-core)

  • ER stress / UPR: regulates ERN1/IRE1-alpha stability (UFM1-dependent), inhibiting the IRE1 UPR arm [PMID:28128204; PMID:32160526].
  • Reticulophagy (CYB5R3 ufmylation) PMID:36543799.
  • NF-kappaB: modulates NFKBIA/IkappaB-alpha stability PMID:23675531.
  • Cartilage development via SOX9 stabilization; biallelic LoF β†’ Shohat-type spondyloepimetaphyseal dysplasia (SEMDSH) PMID:28263186.

Localization

ER membrane (principal). HPA also reports ER, nucleolus; TAS cytoplasm (consistent with the large cytoplasmic domain).

Core function conclusion

Core MFs: GO:0044389 ubiquitin-like protein ligase binding (UFL1 binding/adaptor) and
GO:0141185 UFM1-modified protein reader activity (UFIM). Site: ER membrane.

Pn Notes

(DDRGK1-pn-notes.md)

DDRGK1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q96HY6
  • 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: DDRGK1 (DDRGK domain-containing protein 1; also called UFBP1, Dashurin) is a single-pass endoplasmic-reticulum membrane protein that is an obligate component of the UFM1 ribosome E3 ligase (UREL) complex, together with the E3 ligase UFL1 and CDK5RAP3. DDRGK1 tethers the complex to the ER membrane through its N-terminal transmembrane helix, thereby restricting ufmylation activity to ER-docked ribosomes, and stabilizes UFL1. Following mono-ufmylation of the 60S ribosomal protein RPL26/uL24, DDRGK1 acts as a UFM1 reader, in that its UFM1-interacting motif (UFIM) binds ufmylated RPL26, producing stable association of the 60S subunit with the UREL complex and promoting release and recycling of the large subunit from SEC61 translocons. DDRGK1 is itself a substrate of ufmylation (at Lys-267). Through ER-resident ufmylation it participates in ribosome recycling, reticulophagy (ER-phagy), the response to ER stress and the unfolded protein response (regulating IRE1-alpha/ERN1 stability). Biallelic loss-of-function variants cause Shohat-type spondyloepimetaphyseal dysplasia, reflecting a role in cartilage development via SOX9 stabilization.
  • Existing/core annotation action counts: ACCEPT: 27; KEEP_AS_NON_CORE: 55

PN Consistency Summary

  • Consistency: Strong agreement. Notes, review, dossier, and projections all converge on DDRGK1 as the obligate ER-membrane UFM1-ligase cofactor / UFM1 reader. Review captures every projected term as an existing annotation (GO:0071569 ufmylation ACCEPT; GO:0061709 reticulophagy KEEP_AS_NON_CORE; ribosome-recycling/RQC via GO:0072344, GO:0032790). No contradictions.
  • PN story / NEW pressure: The RQC group projects GO:0006515 protein QC as new_to_goa. GOA already carries the specific RQC outputs GO:0072344 (rescue of stalled cytosolic ribosome) and GO:0032790 (ribosome disassembly), both reviewed. Adding the broad GO:0006515 umbrella would be a less-informative parent of terms already present β€” over-reaches; the RQC role is already captured at greater specificity. GO:0071569 and GO:0061709 are already_in_goa_exact. No defensible NEW term.
  • Evidence alignment: Excellent overlap. Dossier ERphagy ref PMID:32160526 and UFMylation-cofactor refs PMID:36121123 / PMID:38383789 are all present, verified, and HIGH-relevance in the review.
  • Verdict: Consistent and high quality; only the broad GO:0006515 RQC projection over-reaches relative to existing specific GOA terms. Recommended edits: [MAP] drop/downgrade GO:0006515 projection for DDRGK1 (specific RQC terms GO:0072344/GO:0032790 already in GOA and reviewed).

Full Consistency Review

  • UniProt: Q96HY6 Β· batch: proteostasis-batch-2026-06-07c Β· review status: COMPLETE (large, well-evidenced review; 60+ annotations)
  • PN placement: 4 rows across TR/ALP/UPS β€” Translation|Cytosolic translation|Ribosome-associated QC|UFMylation; ALP|...|ERphagy|UFMylation of ER proteins; two UPS ...|UFMylation cofactor rows ; PN-node mapping: types mapped to GO:0071569 protein ufmylation and GO:0061709 reticulophagy (ok_for_propagation); RQC group β†’ GO:0006515 protein QC (ok); UPS nodes no_mapping/context_only.
  • Consistency: Strong agreement. Notes, review, dossier, and projections all converge on DDRGK1 as the obligate ER-membrane UFM1-ligase cofactor / UFM1 reader. Review captures every projected term as an existing annotation (GO:0071569 ufmylation ACCEPT; GO:0061709 reticulophagy KEEP_AS_NON_CORE; ribosome-recycling/RQC via GO:0072344, GO:0032790). No contradictions.
  • PN story / NEW pressure: The RQC group projects GO:0006515 protein QC as new_to_goa. GOA already carries the specific RQC outputs GO:0072344 (rescue of stalled cytosolic ribosome) and GO:0032790 (ribosome disassembly), both reviewed. Adding the broad GO:0006515 umbrella would be a less-informative parent of terms already present β€” over-reaches; the RQC role is already captured at greater specificity. GO:0071569 and GO:0061709 are already_in_goa_exact. No defensible NEW term.
  • Mapping strategy: Mapped status/scope for ufmylation and reticulophagy is correct. The RQC-group β†’ GO:0006515 projection is broader than this gene's reviewed annotations (cf. TOMM20/HSPA8/RAB7A broader-rejection precedent); recommend NOT projecting GO:0006515 onto DDRGK1.
  • Evidence alignment: Excellent overlap. Dossier ERphagy ref PMID:32160526 and UFMylation-cofactor refs PMID:36121123 / PMID:38383789 are all present, verified, and HIGH-relevance in the review.
  • Verdict: Consistent and high quality; only the broad GO:0006515 RQC projection over-reaches relative to existing specific GOA terms. Recommended edits: [MAP] drop/downgrade GO:0006515 projection for DDRGK1 (specific RQC terms GO:0072344/GO:0032790 already in GOA and reviewed).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/DDRGK1/DDRGK1-ai-review.yaml
  • PN workbook rows: 4

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

  • UniProt: Q96HY6
  • In branches: TR, ALP, UPS
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|UFMylation
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0071569 protein ufmylation]
      rationale: This PN RQC type denotes UFM1 conjugation in ribosome quality control. Protein ufmylation is the shared process 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: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | ERphagy | UFMylation of ER proteins

  • UniProt: Q96HY6
  • In branches: TR, ALP, UPS
  • Notes: Involved in reticulophagy, brings UFL1 ligase to ER surface to UFMylate RPN1 and RPL26
  • PN references (titles):
    • A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation - PubMed (nih.gov)
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|UFMylation of ER proteins
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: This PN subtype captures a specific ER-cargo marking mechanism used in ERphagy. Because GO uses reticulophagy for ER autophagy, this subtype can propagate to reticulophagy.
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: The PN ERphagy marking category captures factors that mark ER cargo for selective autophagic turnover. GO uses reticulophagy for this pathway, so propagation to reticulophagy is appropriate.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | UBL modifier cofactors | UFMylation cofactor | transmembrane

  • UniProt: Q96HY6
  • In branches: TR, ALP, UPS
  • Signature domains: (none)
  • Auxiliary domains: IPR019153
  • PN references (titles):
    • 36121123
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|UBL modifier cofactors|UFMylation cofactor|transmembrane
      status=no_mapping scope= GO=[]
      rationale: Reviewed manually as a UPS source node. No single GO term is appropriate for direct propagation from this PN label without narrower context or gene-level evidence.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|UBL modifier cofactors|UFMylation cofactor
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|UBL modifier cofactors
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
    • [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.

PN row 4: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase / UBLM | UFMylation cofactor | UFM1 binding

  • UniProt: Q96HY6
  • In branches: TR, ALP, UPS
  • Signature domains: PMID: 38383789
  • Auxiliary domains: IPR019153
  • PN references (titles):
    • 38383789
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase / UBLM|UFMylation cofactor|UFM1 binding
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a binding-branch UBL-modifier subtype. Because this context mixes catalytic ligases and cofactors, no direct GO propagation is made from this node.
    • [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase / UBLM|UFMylation cofactor
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a binding-branch UBL-modifier subtype. Because this context mixes catalytic ligases and cofactors, no direct GO propagation is made from this node.
    • [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase / UBLM
      status=context_only scope=too_broad_to_propagate GO=[GO:0019787 ubiquitin-like protein transferase activity]
      rationale: This binding-branch group records E3/UBL-modifier context, but it includes cofactors as well as catalytic ligases. Direct propagation should come from narrower enzyme-specific nodes.
    • [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
      status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
      rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
    • [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 (4)

  • 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:0071569 protein ufmylation | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|UFMylation
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|UFMylation of ER proteins

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.

πŸ“„ View Raw YAML

 
id: Q96HY6
gene_symbol: DDRGK1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DDRGK1 (DDRGK domain-containing protein 1; also called UFBP1, Dashurin) is a single-pass endoplasmic-reticulum membrane protein that is an obligate component of the UFM1 ribosome E3 ligase (UREL) complex, together with the E3 ligase UFL1 and CDK5RAP3. DDRGK1 tethers the complex to the ER membrane through its N-terminal transmembrane helix, thereby restricting ufmylation activity to ER-docked ribosomes, and stabilizes UFL1. Following mono-ufmylation of the 60S ribosomal protein RPL26/uL24, DDRGK1 acts as a UFM1 reader, in that its UFM1-interacting motif (UFIM) binds ufmylated RPL26, producing stable association of the 60S subunit with the UREL complex and promoting release and recycling of the large subunit from SEC61 translocons. DDRGK1 is itself a substrate of ufmylation (at Lys-267). Through ER-resident ufmylation it participates in ribosome recycling, reticulophagy (ER-phagy), the response to ER stress and the unfolded protein response (regulating IRE1-alpha/ERN1 stability). Biallelic loss-of-function variants cause Shohat-type spondyloepimetaphyseal dysplasia, reflecting a role in cartilage development via SOX9 stabilization.
existing_annotations:
- term:
    id: GO:0044389
    label: ubiquitin-like protein ligase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DDRGK1 binds the UFM1 E3 ligase UFL1 directly via its C-terminal region, forming the core of the UREL complex. This binding is central to DDRGK1's adaptor function.
    action: ACCEPT
    reason: Direct, experimentally documented binding to the E3 ligase UFL1; this ligase-binding/adaptor activity is a core molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Mediates interaction with UFL1
- term:
    id: GO:0051216
    label: cartilage development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: DDRGK1 is required for cartilage development; loss-of-function variants cause Shohat-type spondyloepimetaphyseal dysplasia, and DDRGK1 stabilizes SOX9.
    action: KEEP_AS_NON_CORE
    reason: A genuine, disease-supported developmental role, but a downstream physiological outcome rather than DDRGK1's core molecular adaptor/reader function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Plays a role in cartilage development through SOX9
- term:
    id: GO:1903895
    label: negative regulation of IRE1-mediated unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: DDRGK1 regulates ERN1/IRE1-alpha stability in a UFM1-dependent manner, modulating the IRE1 arm of the unfolded protein response.
    action: KEEP_AS_NON_CORE
    reason: A valid downstream signaling role mediated by DDRGK1's adaptor function; non-core relative to the molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: regulating ERN1/IRE1-alpha stability
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: DDRGK1 is a single-pass ER membrane protein; this is its principal site of action where it tethers the UREL complex.
    action: ACCEPT
    reason: ER membrane localization is well established experimentally and is essential to restrict ufmylation to ER-docked ribosomes.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real high-throughput interactions but the term is uninformative; core MF is captured by UFL1 binding and UFM1-reader activity.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35156780
  qualifier: enables
  review:
    summary: High-throughput interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction record but uninformative term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:35156780
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36012204
  qualifier: enables
  review:
    summary: High-throughput interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction record but uninformative term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:36012204
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37595036
  qualifier: enables
  review:
    summary: Interaction reported in the mechanistic UREL-complex study (UFL1/CDK5RAP3 partners). Bare term uninformative but reflects cascade interactions.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interactions; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:37595036
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction record but uninformative term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: ER localization, consistent with DDRGK1's role as an ER-membrane-anchored adaptor.
    action: ACCEPT
    reason: Correct compartment; agrees with stronger experimental ER-membrane evidence.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DDRGK1 functions in ER-stress-associated ufmylation and reticulophagy.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core relative to the molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Anti-apoptotic role inferred electronically/by similarity; not directly established for human DDRGK1's core function.
    action: KEEP_AS_NON_CORE
    reason: Plausible downstream effect via ER homeostasis; peripheral and electronically inferred.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0043066 negative regulation of apoptotic process biological_process ECO:0000501 IEA
- term:
    id: GO:0051216
    label: cartilage development
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Cartilage development, also captured by IBA and IMP evidence.
    action: KEEP_AS_NON_CORE
    reason: Genuine developmental role; non-core relative to molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Plays a role in cartilage development through SOX9
- term:
    id: GO:1900100
    label: positive regulation of plasma cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Role in B-cell-to-plasma-cell differentiation via ER expansion and UPR regulation, inferred by similarity.
    action: KEEP_AS_NON_CORE
    reason: Plausible immune-differentiation role by orthology; downstream and non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: promoting differentiation of B-cells into plasma cells
- term:
    id: GO:1903895
    label: negative regulation of IRE1-mediated unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic support for the IRE1-UPR regulatory role also documented experimentally.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream signaling role; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: regulating ERN1/IRE1-alpha stability
- term:
    id: GO:1903898
    label: negative regulation of PERK-mediated unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Regulation of the PERK arm of the UPR, inferred by similarity.
    action: KEEP_AS_NON_CORE
    reason: Plausible UPR-modulating role by orthology; downstream and non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: regulating the unfolded protein response
- term:
    id: GO:1905552
    label: positive regulation of protein localization to endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DDRGK1 promotes protein localization to the ER, inferred electronically; consistent with its ER-tethering role.
    action: KEEP_AS_NON_CORE
    reason: Plausible but electronically inferred; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:1905552 positive regulation of protein localization to endoplasmic reticulum
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (HPA) immunofluorescence ER localization.
    action: ACCEPT
    reason: IDA-supported ER localization consistent with site of action.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA GO_REF:0000052
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:20018847
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization from the paper identifying the UFM1 E3 ligase.
    action: ACCEPT
    reason: Direct experimental support for the principal compartment.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: DDRGK1 modulates NF-kappaB activity through regulation of NFKBIA/IkappaB-alpha stability.
    action: KEEP_AS_NON_CORE
    reason: A documented signaling role but downstream of and separable from DDRGK1's core UREL-adaptor function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: May play a role in NF-
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:36121123
  qualifier: involved_in
  review:
    summary: DDRGK1 is required as a UREL-complex component for protein ufmylation.
    action: ACCEPT
    reason: Direct evidence for DDRGK1's role in the ufmylation process.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:1990234
    label: transferase complex
  evidence_type: IPI
  original_reference_id: PMID:36121123
  qualifier: part_of
  review:
    summary: DDRGK1 is part of the UREL transferase complex (with UFL1 and CDK5RAP3).
    action: ACCEPT
    reason: DDRGK1 is a bona fide subunit of the UFM1 E3 ligase (transferase) complex.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:1990234 transferase complex cellular_component ECO:0000353 IPI PMID:36121123
- term:
    id: GO:0141185
    label: UFM1-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:36121123
  qualifier: enables
  review:
    summary: DDRGK1 reads ufmylated RPL26/uL24 via its UFM1-interacting motif (UFIM), a defining molecular function of the adaptor.
    action: ACCEPT
    reason: Direct evidence for UFM1-modified protein reader activity; this is a core molecular function of DDRGK1.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: DDRGK1 specifically binds to ufmylated RPL26/uL24 via its UFIM motif
- term:
    id: GO:0141185
    label: UFM1-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: enables
  review:
    summary: Reader activity for ufmylated substrate via the UFIM, demonstrated in the CYB5R3/ER-phagy study.
    action: ACCEPT
    reason: Direct support for the core UFM1-reader molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
- term:
    id: GO:0141185
    label: UFM1-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:37595036
  qualifier: enables
  review:
    summary: UFIM-dependent reading of ufmylated RPL26 demonstrated mechanistically.
    action: ACCEPT
    reason: Direct support for the core reader molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
- term:
    id: GO:0141185
    label: UFM1-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: enables
  review:
    summary: Cryo-EM of the UREL-60S complex shows DDRGK1 UFIM binding ufmylated RPL26.
    action: ACCEPT
    reason: Direct structural support for the core reader molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
- term:
    id: GO:0141185
    label: UFM1-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: enables
  review:
    summary: Structural demonstration of DDRGK1 reading ufmylated RPL26 in the UREL-60S complex.
    action: ACCEPT
    reason: Direct structural support for the core reader molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
- term:
    id: GO:1900100
    label: positive regulation of plasma cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Plasma-cell differentiation role transferred from ortholog by sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream and non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: promoting differentiation of B-cells into plasma cells
- term:
    id: GO:1903898
    label: negative regulation of PERK-mediated unfolded protein response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: PERK-UPR regulation transferred from ortholog by sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream and non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: regulating the unfolded protein response
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:35753586
  qualifier: involved_in
  review:
    summary: DDRGK1 (UREL component) required for ufmylation of P4HB.
    action: ACCEPT
    reason: Direct evidence for the ufmylation process role.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:37795761
  qualifier: involved_in
  review:
    summary: DDRGK1 (UREL component) required for ufmylation of HRD1/SYVN1.
    action: ACCEPT
    reason: Direct evidence for the ufmylation process role.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: is_active_in
  review:
    summary: DDRGK1 acts at the ER membrane within the UREL complex.
    action: ACCEPT
    reason: Direct evidence for the site of action.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: DDRGK1 tethers the complex to the endoplasmic reticulum membrane
- term:
    id: GO:0045732
    label: positive regulation of protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: involved_in
  review:
    summary: DDRGK1-mediated ufmylation promotes lysosomal degradation of ufmylated proteins (reticulophagy).
    action: KEEP_AS_NON_CORE
    reason: A downstream consequence of ER ufmylation/reticulophagy; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: thereby promoting lysosomal degradation of ufmylated proteins
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: involved_in
  review:
    summary: DDRGK1 (UREL component) required for ufmylation of CYB5R3.
    action: ACCEPT
    reason: Direct evidence for the ufmylation process role.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:37595036
  qualifier: involved_in
  review:
    summary: DDRGK1 required for RPL26 ufmylation/ribosome-associated quality control.
    action: ACCEPT
    reason: Direct evidence for the ufmylation process role.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37595036
  qualifier: involved_in
  review:
    summary: DDRGK1, within UREL, contributes to recycling of stalled/post-termination 60S ribosomes at the ER. GOA cross-references this as rescue of stalled ribosome.
    action: KEEP_AS_NON_CORE
    reason: A genuine role in ribosome recycling/RQC; captured as a downstream process while the core MF is the UFM1-reader/adaptor activity.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: plays a key role in ribosome recycling by mediating mono-ufmylation of the RPL26/uL24 subunit
- term:
    id: GO:0140501
    label: positive regulation of reticulophagy
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: involved_in
  review:
    summary: DDRGK1-dependent ufmylation promotes reticulophagy (ER-phagy).
    action: KEEP_AS_NON_CORE
    reason: Valid downstream process; non-core relative to molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: is_active_in
  review:
    summary: DDRGK1 acts at the ER membrane within the UREL-60S complex.
    action: ACCEPT
    reason: Direct structural evidence for the site of action.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: DDRGK1 tethers the complex to the endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: is_active_in
  review:
    summary: DDRGK1 acts at the ER membrane within the UREL-60S complex.
    action: ACCEPT
    reason: Direct structural evidence for the site of action.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: DDRGK1 tethers the complex to the endoplasmic reticulum membrane
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: UREL-mediated ufmylation promotes dissociation/release of the 60S subunit from the ER translocon.
    action: KEEP_AS_NON_CORE
    reason: Genuine role in 60S release/recycling; downstream process, non-core relative to the reader/adaptor MF.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: dissociation of the 60S ribosome subunit from the endoplasmic reticulum membrane
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: involved_in
  review:
    summary: UREL-mediated ufmylation promotes 60S release from the ER translocon.
    action: KEEP_AS_NON_CORE
    reason: Genuine role in 60S release/recycling; downstream process, non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: dissociation of the 60S ribosome subunit from the endoplasmic reticulum membrane
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:30626644
  qualifier: involved_in
  review:
    summary: DDRGK1 is required for ufmylation; RPL26 is the principal target.
    action: ACCEPT
    reason: Functional support for DDRGK1's role in ufmylation.
    supported_by:
    - reference_id: PMID:30626644
      supporting_text: Ribosomal protein RPL26 is the principal target of UFMylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: DDRGK1 (UREL component) required for RPL26 ufmylation.
    action: ACCEPT
    reason: Direct evidence for the ufmylation process role.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: involved_in
  review:
    summary: DDRGK1 (UREL component) required for RPL26 ufmylation.
    action: ACCEPT
    reason: Direct evidence for the ufmylation process role.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: DDRGK1, within UREL, contributes to recycling of post-termination/stalled 60S ribosomes at the ER.
    action: KEEP_AS_NON_CORE
    reason: Genuine ribosome-recycling/RQC role; downstream process, non-core relative to the reader/adaptor MF.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: plays a key role in ribosome recycling by mediating mono-ufmylation of the RPL26/uL24 subunit
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: involved_in
  review:
    summary: DDRGK1, within UREL, contributes to release/recycling of stalled 60S ribosomes from the ER translocon.
    action: KEEP_AS_NON_CORE
    reason: Genuine ribosome-recycling/RQC role; downstream process, non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: promoting release and recycling of the large ribosomal subunit
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28128204
  qualifier: enables
  review:
    summary: Interaction with ERN1/IRE1-alpha (UFM1-dependent). Bare term uninformative but reflects a functionally important interaction.
    action: KEEP_AS_NON_CORE
    reason: Real, mechanistically relevant interaction; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28128204
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32160526
  qualifier: enables
  review:
    summary: Interaction with UFL1 from the ER-phagy screen. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interaction; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32160526
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: located_in
  review:
    summary: ER membrane localization from the ER-phagy screen.
    action: ACCEPT
    reason: Direct evidence for principal compartment.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IDA
  original_reference_id: PMID:28128204
  qualifier: involved_in
  review:
    summary: DDRGK1 regulates ERN1/IRE1-alpha stability in a UFM1-dependent manner.
    action: KEEP_AS_NON_CORE
    reason: Documented regulatory role; downstream of the adaptor function, non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: regulating ERN1/IRE1-alpha stability
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:28128204
  qualifier: involved_in
  review:
    summary: DDRGK1 functions in ER homeostasis/UPR via IRE1-alpha.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: A critical role of DDRGK1 in endoplasmic reticulum homoeostasis
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: DDRGK1 functions in ER-stress-associated ufmylation/reticulophagy.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: DDRGK1 contributes to reticulophagy driven by ER ufmylation.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream process; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0070972
    label: protein localization to endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: DDRGK1 promotes protein localization to the ER.
    action: KEEP_AS_NON_CORE
    reason: Plausible role consistent with ER-tethering; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0070972 protein localization to endoplasmic reticulum biological_process ECO:0000314 IDA PMID:32160526
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: DDRGK1 required for ufmylation in the ER-phagy context.
    action: ACCEPT
    reason: Direct evidence for the ufmylation process role.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:1903895
    label: negative regulation of IRE1-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:28128204
  qualifier: involved_in
  review:
    summary: DDRGK1 negatively regulates the IRE1 arm of the UPR via control of IRE1-alpha stability.
    action: KEEP_AS_NON_CORE
    reason: Documented signaling role; downstream, non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability
- term:
    id: GO:1903895
    label: negative regulation of IRE1-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: ER-phagy screen supports negative regulation of the IRE1 UPR arm.
    action: KEEP_AS_NON_CORE
    reason: Documented signaling role; downstream, non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28263186
  qualifier: enables
  review:
    summary: Interaction with SOX9 (from the SEMDSH/cartilage study). Bare term uninformative but reflects a functionally relevant interaction.
    action: KEEP_AS_NON_CORE
    reason: Real interaction relevant to the cartilage role; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28263186
- term:
    id: GO:0032435
    label: negative regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:28263186
  qualifier: involved_in
  review:
    summary: DDRGK1 inhibits ubiquitin-mediated proteasomal degradation of SOX9, stabilizing it.
    action: KEEP_AS_NON_CORE
    reason: Documented effect underlying the cartilage role; downstream, non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator
- term:
    id: GO:0051216
    label: cartilage development
  evidence_type: IMP
  original_reference_id: PMID:28263186
  qualifier: involved_in
  review:
    summary: Loss of DDRGK1 causes SEMDSH; DDRGK1 acts in cartilage development through SOX9.
    action: KEEP_AS_NON_CORE
    reason: Genuine disease-supported developmental role; non-core relative to molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Plays a role in cartilage development through SOX9
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: Inferred from DDRGK1's modulation of NF-kappaB-dependent transcription.
    action: KEEP_AS_NON_CORE
    reason: Indirect, downstream transcriptional effect via NF-kappaB signaling; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: May play a role in NF-
- term:
    id: GO:1902808
    label: positive regulation of cell cycle G1/S phase transition
  evidence_type: IC
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: Inferred (IC) cell-cycle effect downstream of DDRGK1's NF-kappaB/proliferation role.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream effect; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:1902808 positive regulation of cell cycle G1/S phase transition biological_process ECO:0000305 IC PMID:23675531
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: DDRGK1 promotes cell migration in the NF-kappaB study.
    action: KEEP_AS_NON_CORE
    reason: Downstream cellular phenotype; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0030335 positive regulation of cell migration biological_process ECO:0000315 IMP PMID:23675531
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23675531
  qualifier: enables
  review:
    summary: Interaction with NFKBIA/IkappaB-alpha. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction relevant to the NF-kappaB role; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:23675531
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:23675531
  qualifier: located_in
  review:
    summary: Cytoplasmic localization asserted in the NF-kappaB study; DDRGK1 is an ER-membrane protein with a large cytoplasmic domain.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic-facing topology, but the principal compartment is the ER membrane.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Cytoplasmic
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: DDRGK1 promotes proliferation in the NF-kappaB study.
    action: KEEP_AS_NON_CORE
    reason: Downstream cellular phenotype; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0008284 positive regulation of cell population proliferation biological_process ECO:0000315 IMP PMID:23675531
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: Gene-expression effects downstream of NF-kappaB modulation.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream effect; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0010628 positive regulation of gene expression biological_process ECO:0000315 IMP PMID:23675531
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: Gene-expression effects downstream of NF-kappaB modulation.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream effect; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0010629 negative regulation of gene expression biological_process ECO:0000315 IMP PMID:23675531
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: DDRGK1 promotes NFKBIA proteasomal degradation in the NF-kappaB study.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect within NF-kappaB signaling; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process biological_process ECO:0000315 IMP PMID:23675531
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Anti-apoptotic role transferred from ortholog by sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream and non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0043066 negative regulation of apoptotic process biological_process ECO:0000250 ISS GO_REF:0000024
- term:
    id: GO:1905552
    label: positive regulation of protein localization to endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Transferred from ortholog by sequence similarity; consistent with ER-tethering role.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:1905552 positive regulation of protein localization to endoplasmic reticulum biological_process ECO:0000250 ISS GO_REF:0000024
- term:
    id: GO:1990592
    label: protein K69-linked ufmylation
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: DDRGK1 participates in UFM1 conjugation, including K69-linked UFM1 chains.
    action: KEEP_AS_NON_CORE
    reason: Specific chain-linkage sub-aspect of ufmylation; narrow process annotation.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:1990592 protein K69-linked ufmylation biological_process ECO:0000314 IDA PMID:25219498
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20228063
  qualifier: enables
  review:
    summary: Interaction with CDK5RAP3 (a UREL component). Bare term uninformative but reflects a cascade interaction.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interaction; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20228063
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:20228063
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization.
    action: ACCEPT
    reason: Direct evidence for principal compartment.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0033146
    label: regulation of intracellular estrogen receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: DDRGK1 contributes to ufmylation of ASC1/TRIP4, affecting ERalpha transactivation.
    action: KEEP_AS_NON_CORE
    reason: A documented but specialized signaling role downstream of ufmylation; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: May also be required for TRIP4 ufmylation
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ER stress response transferred from ortholog by sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context by orthology; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:1901800
    label: positive regulation of proteasomal protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: DDRGK1 promotes proteasomal catabolism of NFKBIA in the NF-kappaB study.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect within NF-kappaB signaling; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:1901800 positive regulation of proteasomal protein catabolic process biological_process ECO:0000315 IMP PMID:23675531
- term:
    id: GO:1903721
    label: positive regulation of I-kappaB phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:23675531
  qualifier: involved_in
  review:
    summary: DDRGK1 promotes IkappaB-alpha phosphorylation, activating NF-kappaB.
    action: KEEP_AS_NON_CORE
    reason: Downstream signaling effect; non-core.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:1903721 positive regulation of I-kappaB phosphorylation biological_process ECO:0000315 IMP PMID:23675531
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: Interaction with UFL1/TRIP4 in the ASC1/ufmylation study. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade-relevant interaction; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25219498
- term:
    id: GO:0044389
    label: ubiquitin-like protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: Direct interaction with the UFM1 E3 ligase UFL1, the core adaptor binding activity of DDRGK1.
    action: ACCEPT
    reason: Direct experimental support for the core UFL1-binding/adaptor molecular function.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: Mediates interaction with UFL1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20018847
  qualifier: enables
  review:
    summary: Interaction with UFL1 from the paper identifying the UFM1 E3 ligase. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interaction; non-core under generic term.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20018847
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:20018847
  qualifier: located_in
  review:
    summary: Experimental ER localization from the UFM1 E3 ligase paper.
    action: ACCEPT
    reason: Direct evidence for principal compartment.
    supported_by:
    - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:20018847
  title: A novel type of E3 ligase for the Ufm1 conjugation system.
  findings:
  - statement: DDRGK1 interacts with the UFM1 E3 ligase UFL1 and is ufmylated at Lys-267; it localizes to the ER.
    reference_section_type: ABSTRACT
- id: PMID:20228063
  title: A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling.
  findings:
  - statement: DDRGK1 interacts with CDK5RAP3/C53 and its stability is co-regulated; it modulates NF-kappaB signaling.
    reference_section_type: ABSTRACT
- id: PMID:23675531
  title: DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha stability.
  findings:
  - statement: DDRGK1 modulates NF-kappaB activity by regulating NFKBIA/IkappaB-alpha stability.
    reference_section_type: ABSTRACT
- id: PMID:25219498
  title: Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
  findings:
  - statement: DDRGK1 interacts with UFL1 and is required for TRIP4/ASC1 ufmylation, affecting ERalpha transactivation.
    reference_section_type: ABSTRACT
- id: PMID:28128204
  title: A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1alpha stability.
  findings:
  - statement: DDRGK1 interacts with ERN1/IRE1-alpha in a UFM1-dependent manner and regulates its stability, inhibiting the IRE1 arm of the UPR.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Title plausibly establishes the DDRGK1-IRE1alpha/UPR regulatory role, but the publication is not cached and no PMID-anchored GOA evidence ties this claim to a checkable source, so correctness is not yet VERIFIED.
- id: PMID:28263186
  title: Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia.
  findings:
  - statement: Loss-of-function DDRGK1 variants cause Shohat-type spondyloepimetaphyseal dysplasia; DDRGK1 stabilizes SOX9 by inhibiting its ubiquitin-mediated degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Disease gene paper establishing the cartilage/SOX9 role.
- id: PMID:30626644
  title: Ribosomal protein RPL26 is the principal target of UFMylation.
  findings:
  - statement: RPL26 is the principal cellular target of UFMylation.
    reference_section_type: TITLE
- id: PMID:32160526
  title: A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-Resident UFMylation.
  findings:
  - statement: DDRGK1 and ER-resident UFMylation are required for ER-phagy and IRE1 UPR regulation.
    reference_section_type: ABSTRACT
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35156780
  title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system.
  findings: []
- id: PMID:35753586
  title: P4HB UFMylation regulates mitochondrial function and oxidative stress.
  findings: []
- id: PMID:36012204
  title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters.
  findings: []
- id: PMID:36121123
  title: A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
  findings:
  - statement: DDRGK1 is a component of the UREL complex and reads ufmylated RPL26 via its UFIM motif.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines DDRGK1 as the UFM1 reader within the scaffold E3 complex.
- id: PMID:36543799
  title: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
  findings:
  - statement: DDRGK1 UFIM reads ufmylated substrate; UREL-dependent ufmylation of CYB5R3 drives ER-phagy.
    reference_section_type: ABSTRACT
- id: PMID:37595036
  title: Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control.
  findings:
  - statement: DDRGK1 UFIM-dependent reading of ufmylated RPL26 stabilizes 60S-UREL association and supports ribosome-associated quality control.
    reference_section_type: ABSTRACT
- id: PMID:37795761
  title: UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
  findings: []
- id: PMID:38383785
  title: UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.
  findings:
  - statement: Cryo-EM of the UREL-60S complex shows DDRGK1 tethering and UFIM reading of ufmylated RPL26 to promote 60S recycling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis of DDRGK1 ER-tethering and reader roles.
- id: PMID:38383789
  title: The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
  findings:
  - statement: UREL (UFL1/DDRGK1/CDK5RAP3) ufmylates RPL26 to release/recycle 60S ribosomes from ER translocons; DDRGK1 single-pass membrane anchor and UFIM are key.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structure of DDRGK1 in the UREL-60S complex.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
core_functions:
- description: Obligate ER-membrane-anchored cofactor/substrate-adaptor of the UFM1 E3 ligase that binds the E3 ligase UFL1 (and CDK5RAP3) to form the UREL complex, tethering ufmylation activity to ER-docked ribosomes and stabilizing UFL1.
  molecular_function:
    id: GO:0044389
    label: ubiquitin-like protein ligase binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
    supporting_text: Mediates interaction with UFL1
  - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
    supporting_text: DDRGK1 tethers the complex to the endoplasmic reticulum membrane
- description: UFM1-modified protein reader that, via its UFM1-interacting motif (UFIM), specifically binds ufmylated RPL26/uL24 on the 60S ribosome, producing stable association of the 60S subunit with the UREL complex and promoting release/recycling of the large subunit from the ER translocon.
  molecular_function:
    id: GO:0141185
    label: UFM1-modified protein reader activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/DDRGK1/DDRGK1-uniprot.txt
    supporting_text: The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24
proposed_new_terms: []
suggested_questions:
- question: Is ufmylation of DDRGK1 at Lys-267 functionally required for UREL activity or is it a collateral consequence of the reaction it scaffolds?
- question: How are the ER-stress/UPR (IRE1-alpha), NF-kappaB and SOX9/cartilage roles of DDRGK1 related to its UREL ribosome-recycling function - are they separable activities or downstream consequences of ER ufmylation?
suggested_experiments:
- description: Separation-of-function mutants (UFIM-dead vs UFL1-binding-dead vs Lys-267 ufmylation-dead) tested in 60S-recycling, IRE1-alpha-stability and SOX9-stability assays to dissect which DDRGK1 activities drive each phenotype.
- description: Reconstitute the UREL-60S complex with purified components to quantify the contribution of DDRGK1 membrane-tethering and UFIM reading to RPL26 ufmylation kinetics and 60S release from SEC61.