RNF41

UniProt ID: Q9H4P4
Organism: Homo sapiens
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene Description

RNF41 (RING finger protein 41; also known as NRDP1, neuregulin receptor degradation protein-1, and FLRF) is a 317-residue RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27). It has an N-terminal RING-type zinc finger (catalytic residues Cys34/His36/Asp56) that recruits a ubiquitin-charged E2 conjugating enzyme, a degenerate SIAH-type zinc finger, and a C-terminal dimerization/substrate-binding domain that engages substrates and the deubiquitinase USP8. RNF41 directs ubiquitination and, for several targets, proteasomal degradation of a defined substrate set. Its best-characterized substrates are the neuregulin receptor tyrosine kinases ErbB3 and ErbB4 (but not EGFR or ErbB2): RNF41 binds the ErbB3 cytoplasmic tail in an activation-independent manner and mediates growth-factor-independent ubiquitination and ER-associated/proteasomal degradation, thereby setting steady-state ErbB3/ErbB4 levels and restraining ErbB2/ErbB3-driven proliferative signaling and tumor growth. RNF41 also ubiquitinates and degrades the giant inhibitor-of-apoptosis protein BIRC6/BRUCE/Apollon, thereby promoting apoptosis, and ubiquitinates the E3 ligase PRKN/Parkin, accelerating its degradation, lowering Parkin activity and increasing reactive oxygen species (linking RNF41 to oxidative stress and Parkinson disease biology and to RNF41-PRKN regulation of late mitophagy). In innate immunity RNF41 polyubiquitinates MYD88 (limiting MyD88-dependent pro-inflammatory cytokines) and promotes TRIF-dependent type I interferon production and TBK1/IRF3 activation, and it ubiquitinates the erythropoietin and interleukin-3 receptors to control hematopoietic progenitor differentiation. RNF41 itself is regulated by autoubiquitination-driven proteasomal turnover that is counteracted by the deubiquitinase USP8 and by sequestration into endoplasmic-reticulum tubules by the reticulon Rtn4A/Nogo-A. It localizes mainly to the cytosol and perinuclear region, with a regulated pool on the ER tubular network.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0071782 endoplasmic reticulum tubular network
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference that RNF41 acts on the ER tubular network. RNF41 ubiquitinates newly synthesized ErbB3 at the ER and can be sequestered into ER tubules by Rtn4A.
Reason: Experimentally supported localization (IDA in PMID:27353365) but represents the Rtn4A-sequestered/ER-associated degradation pool; the dominant active compartment is cytosolic/perinuclear.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0000209 protein polyubiquitination
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA machine-learning assignment of protein polyubiquitination, the core catalytic process of RNF41.
Reason: Core biological process directly demonstrated; RNF41 catalyzes polyubiquitin chain assembly on substrates including Parkin and BRUCE. Redundant with the IDA annotations.
Supporting Evidence:
PMID:18541373
Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
GO:0008270 zinc ion binding
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic assignment of zinc ion binding; RNF41 has a RING-type and a SIAH-type zinc finger that coordinate zinc.
Reason: Structurally required; the RING and SIAH-type zinc fingers coordinate zinc, essential for the RING fold and catalytic activity.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
ZN_FING 18..57
GO:0016567 protein ubiquitination
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic assignment of general protein ubiquitination, a parent of the specific polyubiquitination RNF41 catalyzes.
Reason: Correct but generic; the specific protein polyubiquitination annotation (GO:0000209) better captures the role.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.
GO:0019899 enzyme binding
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: ARBA machine-learning assignment of enzyme binding. RNF41 binds the deubiquitinase USP8 and the E3 ligase Parkin; a generic and uninformative binding term.
Reason: Correct but generic - RNF41 does bind enzymes (USP8, Parkin) - but enzyme binding is uninformative; more specific functional terms capture the biology.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Interacts with USP8, ERBB3, PRKN and BIRC6
GO:0061630 ubiquitin protein ligase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of ubiquitin protein ligase activity, the core molecular function of RNF41 as a RING-type E3 ligase.
Reason: Core molecular function corroborated by direct experimental evidence (IDA); genuine catalytic RING E3 whose RING mutations abolish activity.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:21516116
Next-generation sequencing to generate interactome datasets. 		KEEP AS NON CORE
Summary: High-throughput interactome interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:25036637
A quantitative chaperone interaction network reveals the arc... 		KEEP AS NON CORE
Summary: Chaperone interaction-network study interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: Proteome-scale interactome interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:25910212
Widespread macromolecular interaction perturbations in human... 		KEEP AS NON CORE
Summary: Interactome perturbation study interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:26496610
A human interactome in three quantitative dimensions organiz... 		KEEP AS NON CORE
Summary: Quantitative interactome (stoichiometry/abundance) interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: Interactome-community study interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: Binary interactome reference-map interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: Neurodegeneration interactome interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: Cell-specific interactome interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Multimodal cell-map interactome interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Full=E3 ubiquitin-protein ligase NRDP1
GO:0042802 identical protein binding
IPI
PMID:22493164
Systematic analysis of dimeric E3-RING interactions reveals ... 		KEEP AS NON CORE
Summary: Dimeric E3-RING interaction analysis; RNF41 self-associates (its C-terminal domain dimerizes, also forming trimers via the coiled-coil region). A real, informative homotypic interaction.
Reason: RNF41 genuinely self-associates (homodimer/oligomer), but this is a structural property supporting rather than defining its core ligase function.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266
GO:0042802 identical protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: Proteome-scale interactome self-interaction (RNF41 homodimerization). A real homotypic interaction.
Reason: RNF41 self-associates; supports its function but is not the core catalytic role.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266
GO:0042802 identical protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		KEEP AS NON CORE
Summary: Interaction-perturbation study self-interaction (RNF41 homodimerization).
Reason: RNF41 self-associates; supports its function but is not the core catalytic role.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266
GO:0005128 erythropoietin receptor binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-transferred (Ensembl Compara) erythropoietin receptor binding; RNF41 ubiquitinates the EPO receptor to control hematopoietic progenitor differentiation (By similarity).
Reason: Reflects a real substrate-recognition interaction (EPOR) supporting the hematopoietic role, but is a specific non-core substrate transferred by similarity.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors
GO:0005135 interleukin-3 receptor binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-transferred (Ensembl Compara) interleukin-3 receptor binding; RNF41 ubiquitinates the IL-3 receptor to control hematopoietic progenitor differentiation (By similarity).
Reason: Reflects a real substrate-recognition interaction (IL3RA/CSF2RB) supporting the hematopoietic role, but is a specific non-core substrate transferred by similarity.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors
GO:0004842 ubiquitin-protein transferase activity
TAS
Reactome:R-HSA-1358789 		ACCEPT
Summary: Reactome curation (self-ubiquitination of RNF41) of ubiquitin-protein transferase activity, the core catalytic molecular function.
Reason: Core molecular function; RNF41 is a genuine catalytic RING E3 that transfers ubiquitin from E2 to substrate. Synonymous with ubiquitin protein ligase activity.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
EC=2.3.2.27
GO:0019904 protein domain specific binding
IPI
PMID:27353365
The ER structural protein Rtn4A stabilizes and enhances sign... 		KEEP AS NON CORE
Summary: RNF41 binds the core reticulon domain of Rtn4A via its receptor-binding (C-terminal) domain; a specific domain-domain interaction.
Reason: Records a real, mechanistically relevant interaction (Rtn4A reticulon domain) that regulates RNF41 localization/activity, but is a binding term rather than RNF41's core function.
Supporting Evidence:
PMID:27353365
the core reticulon domain is sufficient for mediating interaction with Nrdp1
GO:0030971 receptor tyrosine kinase binding
IPI
PMID:27353365
The ER structural protein Rtn4A stabilizes and enhances sign... 		KEEP AS NON CORE
Summary: RNF41 binds the receptor tyrosine kinase ErbB3 (and ErbB4) via its C-terminal domain; the substrate-recognition interaction underlying ErbB3/ErbB4 degradation.
Reason: Informative substrate-recognition molecular function (ErbB3/ErbB4 binding) supporting the core ErbB3-degradation role; kept as non-core because the catalytic ligase activity is the defining function.
Supporting Evidence:
PMID:27353365
The C-terminal domain of Nrdp1 is responsible for binding its substrate ErbB3
GO:0045732 positive regulation of protein catabolic process
IMP
PMID:27353365
The ER structural protein Rtn4A stabilizes and enhances sign... 		KEEP AS NON CORE
Summary: RNF41 promotes proteasomal catabolism of ErbB3 (suppressed by Rtn4A). A regulatory framing of its degradative activity.
Reason: Correct but a higher-level regulatory term; the specific proteasomal protein catabolic process annotation better captures the role.
Supporting Evidence:
PMID:27353365
Rtn4A counteracts the Nrdp1-mediated degradation of ErbB3
GO:0048471 perinuclear region of cytoplasm
IDA
PMID:27353365
The ER structural protein Rtn4A stabilizes and enhances sign... 		ACCEPT
Summary: Direct localization of RNF41 to the cytosolic/perinuclear region (before Rtn4A-induced redistribution to ER tubules).
Reason: Experimentally supported core localization; RNF41 is normally cytosolic/perinuclear where it acts on its substrates.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0071782 endoplasmic reticulum tubular network
IDA
PMID:27353365
The ER structural protein Rtn4A stabilizes and enhances sign... 		KEEP AS NON CORE
Summary: Direct evidence that RNF41 localizes to ER tubules upon Rtn4A expression; the Rtn4A-sequestered pool where RNF41 is held inactive.
Reason: Experimentally supported but represents the Rtn4A-sequestered/ERAD pool rather than the dominant cytosolic/perinuclear active site.
Supporting Evidence:
PMID:27353365
Rtn4A sequesters Nrdp1 in ER tubules where it cannot act on its substrates
GO:0061630 ubiquitin protein ligase activity
IDA
PMID:18541373
Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... 		ACCEPT
Summary: Direct evidence that RNF41 acts as a ubiquitin protein ligase, catalyzing poly-ubiquitin chains on Parkin in vitro and in cells. Core molecular function.
Reason: Core molecular function directly demonstrated; RNF41 is a genuine catalytic RING E3 ligase.
Supporting Evidence:
PMID:18541373
Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
GO:0031267 small GTPase binding
IPI
PMID:24056301
The deubiquitylase USP33 discriminates between RALB function... 		UNDECIDED
Summary: An interaction recorded in the USP33/RALB study; RNF41 appears as an interactor. The specific RNF41-small GTPase binding cannot be verified from the cached abstract, which concerns USP33 and the RAS-like GTPase RALB.
Reason: Cannot verify the RNF41-specific small GTPase binding claim from available text (cached entry is abstract-only and centered on USP33/RALB). Per guidelines, an experimental IPI is not removed on the basis of incomplete cached evidence; defer to the curator.
Supporting Evidence:
PMID:24056301
The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection
GO:0000209 protein polyubiquitination
IDA
PMID:18541373
Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... 		ACCEPT
Summary: Direct evidence that RNF41 catalyzes poly-ubiquitin chains on Parkin. Core biological process.
Reason: Core biological process directly demonstrated; RNF41 assembles polyubiquitin chains on its substrate Parkin.
Supporting Evidence:
PMID:18541373
Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
GO:0010498 proteasomal protein catabolic process
IDA
PMID:18541373
Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... 		ACCEPT
Summary: Direct evidence that RNF41 drives proteasome-dependent degradation of Parkin (and, in other studies, ErbB3 and BRUCE). Core biological process.
Reason: Core biological process directly demonstrated; RNF41 targets substrates for proteasomal degradation.
Supporting Evidence:
PMID:18541373
overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner
GO:2000379 positive regulation of reactive oxygen species metabolic process
IMP
PMID:18541373
Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... 		KEEP AS NON CORE
Summary: Nrdp1 overexpression increases ROS production (abrogated by Parkin co-expression), via the RNF41-Parkin axis. A downstream consequence of degrading Parkin.
Reason: Real phenotype but a downstream consequence of RNF41-mediated Parkin degradation, not a core function.
Supporting Evidence:
PMID:18541373
overexpression of Nrdp1 increased the production of reactive oxygen species (ROS), which was abrogated by co-expression of Parkin
GO:0004842 ubiquitin-protein transferase activity
IDA
PMID:24105792
Protein microarray characterization of the S-nitrosoproteome... 		ACCEPT
Summary: Protein-microarray (S-nitrosoproteome) detection of RNF41 ubiquitin-protein transferase activity. The catalytic molecular function is correct, though the source is a proteome-scale assay.
Reason: Core molecular function; consistent with the well-established catalytic RING E3 activity of RNF41, redundant with the IDA ligase-activity annotation.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
EC=2.3.2.27
GO:0051865 protein autoubiquitination
IDA
PMID:24105792
Protein microarray characterization of the S-nitrosoproteome... 		ACCEPT
Summary: RNF41 autoubiquitinates, leading to its own proteasomal degradation (counteracted by USP8). A well-established self-regulatory activity.
Reason: Well-supported activity (autoubiquitination regulates RNF41 levels; RING mutations that disrupt ligase activity stabilize RNF41); consistent with a genuine catalytic RING E3.
Supporting Evidence:
file:human/RNF41/RNF41-uniprot.txt
Autoubiquitinated. Autoubiquitination leads to proteasomal degradation.
GO:0097191 extrinsic apoptotic signaling pathway
IDA
PMID:14765125
Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... 		KEEP AS NON CORE
Summary: RNF41 ubiquitinates and degrades the IAP BRUCE/BIRC6, triggering apoptosis. A downstream process of its degradative activity.
Reason: Real apoptosis-promoting role via BRUCE degradation, but a downstream biological process rather than the core ligase function.
Supporting Evidence:
PMID:14765125
Nrdp1 can be important in the initiation of apoptosis by catalyzing ubiquitination and degradation of BRUCE
GO:0005829 cytosol
TAS
Reactome:R-HSA-1358789 		ACCEPT
Summary: Reactome curation of cytosolic localization (self-ubiquitination of RNF41). Consistent with the core cytosolic site of action.
Reason: Correct core localization; RNF41 is predominantly cytosolic/perinuclear.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0005829 cytosol
TAS
Reactome:R-HSA-1358790 		ACCEPT
Summary: Reactome curation of cytosolic localization (RNF41 ubiquitinates ERBB3). Consistent with the core cytosolic site of action.
Reason: Correct core cytosolic localization where RNF41 acts on its substrates.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0005829 cytosol
TAS
Reactome:R-HSA-1358792 		ACCEPT
Summary: Reactome curation of cytosolic localization (RNF41 ubiquitinates activated ERBB3). Consistent with the core cytosolic site of action.
Reason: Correct core cytosolic localization where RNF41 acts on its substrates.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0005829 cytosol
TAS
Reactome:R-HSA-1358795 		ACCEPT
Summary: Reactome curation of cytosolic localization (deubiquitination of RNF41 by P-USP8). Consistent with the core cytosolic site of action.
Reason: Correct core cytosolic localization where RNF41 acts on its substrates.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0005829 cytosol
TAS
Reactome:R-HSA-1358797 		ACCEPT
Summary: Reactome curation of cytosolic localization (ubiquitinated RNF41 binds P-USP8). Consistent with the core cytosolic site of action.
Reason: Correct core cytosolic localization where RNF41 acts on its substrates.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0005829 cytosol
TAS
Reactome:R-HSA-1358798 		ACCEPT
Summary: Reactome curation of cytosolic localization (RNF41 binds neuregulin-activated ERBB3). Consistent with the core cytosolic site of action.
Reason: Correct core cytosolic localization where RNF41 acts on its substrates.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0005829 cytosol
TAS
Reactome:R-HSA-1358801 		ACCEPT
Summary: Reactome curation of cytosolic localization (ERBB3 binds RNF41 ubiquitin ligase). Consistent with the core cytosolic site of action.
Reason: Correct core cytosolic localization where RNF41 acts on its substrates.
Supporting Evidence:
PMID:27353365
Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
GO:0005515 protein binding
IPI
PMID:11867753
An RBCC protein implicated in maintenance of steady-state ne... 		KEEP AS NON CORE
Summary: Interaction with ErbB3 from the original Nrdp1/RBCC identification study. Bare protein binding is uninformative.
Reason: Records the foundational substrate interaction (ErbB3) but bare protein binding is uninformative; the receptor tyrosine kinase binding term is more specific.
Supporting Evidence:
PMID:11867753
Nrdp1 interacts specifically with the neuregulin receptors ErbB3 and ErbB4
GO:0008285 negative regulation of cell population proliferation
IDA
PMID:17145873
Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... 		KEEP AS NON CORE
Summary: Nrdp1 suppresses ErbB2/ErbB3-dependent breast tumor cell proliferation; loss of Nrdp1 enhances growth. A downstream consequence of ErbB3 degradation.
Reason: Real phenotype (tumor-suppressive) but downstream of RNF41-mediated ErbB3 degradation, not a core molecular function.
Supporting Evidence:
PMID:17145873
overexpression of Nrdp1 in human breast cancer cells results in the suppression of ErbB3 levels, accompanied by the inhibition of cell growth and motility
GO:0030336 negative regulation of cell migration
IMP
PMID:17145873
Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... 		KEEP AS NON CORE
Summary: Nrdp1 inhibits breast tumor cell motility/migration via ErbB3 suppression. A downstream consequence of ErbB3 degradation.
Reason: Real phenotype but downstream of RNF41-mediated ErbB3 degradation, not a core function.
Supporting Evidence:
PMID:17145873
the inhibition of cell growth and motility and the attenuation of signal transduction pathways
GO:0043408 regulation of MAPK cascade
IDA
PMID:17145873
Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... 		KEEP AS NON CORE
Summary: Nrdp1 attenuates ErbB3-driven MAPK signaling. A downstream consequence of ErbB3 degradation.
Reason: Real regulatory effect but downstream of RNF41-mediated ErbB3 degradation, not a core function.
Supporting Evidence:
PMID:17145873
the attenuation of signal transduction pathways
GO:0051896 regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
IDA
PMID:17145873
Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... 		KEEP AS NON CORE
Summary: Nrdp1 attenuates ErbB3-driven PI3K/AKT signaling. A downstream consequence of ErbB3 degradation.
Reason: Real regulatory effect but downstream of RNF41-mediated ErbB3 degradation, not a core function.
Supporting Evidence:
PMID:17145873
the attenuation of signal transduction pathways
GO:2000377 regulation of reactive oxygen species metabolic process
IMP
PMID:18541373
Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... 		KEEP AS NON CORE
Summary: RNF41 regulates ROS levels via the Parkin axis (knockdown lowers ROS). A downstream consequence of degrading Parkin.
Reason: Real phenotype but downstream of RNF41-mediated Parkin degradation; the more specific positive-regulation term also captures this.
Supporting Evidence:
PMID:18541373
suppression of Nrdp1 by shRNA conferred SH-SY5Y cells a lower ROS level
GO:0004842 ubiquitin-protein transferase activity
IDA
PMID:18541373
Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... 		ACCEPT
Summary: Direct evidence of RNF41 ubiquitin-protein transferase activity (catalyzing poly-Ub chains on Parkin). Core molecular function.
Reason: Core molecular function directly demonstrated; genuine catalytic RING E3.
Supporting Evidence:
PMID:18541373
Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
GO:0000209 protein polyubiquitination
IDA
PMID:14765125
Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... 		ACCEPT
Summary: Direct evidence that RNF41 catalyzes ubiquitination of BRUCE/BIRC6. Core biological process.
Reason: Core biological process directly demonstrated; RNF41 ubiquitinates the giant IAP BRUCE.
Supporting Evidence:
PMID:14765125
purified Nrdp1 catalyzes BRUCE ubiquitination
GO:0004842 ubiquitin-protein transferase activity
IDA
PMID:14765125
Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... 		ACCEPT
Summary: Direct evidence that purified RNF41 catalyzes BRUCE ubiquitination with an E2 (UbcH5c). Core molecular function.
Reason: Core molecular function directly demonstrated in a reconstituted assay; genuine catalytic RING E3.
Supporting Evidence:
PMID:14765125
In the presence of an exogenous E2, UbcH5c, purified Nrdp1 catalyzes BRUCE ubiquitination
GO:0005515 protein binding
IPI
PMID:14765125
Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... 		KEEP AS NON CORE
Summary: Interaction with BRUCE/BIRC6 (a substrate). Bare protein binding is uninformative.
Reason: Records a real substrate interaction (BRUCE) but bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
PMID:14765125
Nrdp1 associates with BRUCE/apollon, a 530 kDa membrane-associated IAP
GO:0005515 protein binding
IPI
PMID:15314180
Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiq... 		KEEP AS NON CORE
Summary: Interaction with the deubiquitinase USP8 (which stabilizes RNF41). Bare protein binding is uninformative.
Reason: Records a real, functionally important interaction (USP8) but bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
PMID:15314180
we identified the deubiquitinating enzyme USP8 (also called Ubpy) as a protein that physically interacts with Nrdp1

Core Functions

Functions as a catalytic RING-type E3 ubiquitin-protein ligase that recruits a ubiquitin-charged E2 conjugating enzyme via its N-terminal RING domain (Cys34/His36/Asp56) and transfers ubiquitin to substrate lysines, assembling polyubiquitin chains and directing proteasomal degradation of substrates; also autoubiquitinates to regulate its own levels.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
protein polyubiquitination proteasomal protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:18541373
    Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
  • PMID:14765125
    In the presence of an exogenous E2, UbcH5c, purified Nrdp1 catalyzes BRUCE ubiquitination

Sets steady-state levels of the neuregulin receptor tyrosine kinases ErbB3 and ErbB4 by binding their cytoplasmic tail and mediating growth-factor-independent ubiquitination and ER-associated/proteasomal degradation (specific for ErbB3/ErbB4, not EGFR/ErbB2), thereby restraining ErbB2/ErbB3-driven proliferative signaling.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
proteasomal protein catabolic process
Cellular Locations:
cytosol perinuclear region of cytoplasm
Supporting Evidence:
  • PMID:11867753
    Nrdp1 interacts specifically with the neuregulin receptors ErbB3 and ErbB4
  • PMID:27353365
    The C-terminal domain of Nrdp1 is responsible for binding its substrate ErbB3

Ubiquitinates and degrades the giant inhibitor-of-apoptosis protein BIRC6/BRUCE to promote apoptosis, and ubiquitinates the E3 ligase PRKN/Parkin to accelerate its degradation, lowering Parkin activity and increasing reactive oxygen species.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
protein polyubiquitination
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:14765125
    Nrdp1 can be important in the initiation of apoptosis by catalyzing ubiquitination and degradation of BRUCE
  • PMID:18541373
    overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:11867753
An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels.
  • Identifies Nrdp1/RNF41 as an RBCC RING ligase that binds the ErbB3/ErbB4 cytoplasmic tail (not EGFR/ErbB2) in an activation-independent manner and suppresses steady-state ErbB3/ErbB4 receptor levels.
PMID:14765125
Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis.
  • Nrdp1 binds and (with E2 UbcH5c) ubiquitinates the giant IAP BRUCE/BIRC6, promoting its proteasomal degradation and triggering apoptosis.
PMID:15314180
Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8.
  • Nrdp1 undergoes RING-dependent autoubiquitination and proteasomal degradation; the deubiquitinase USP8 binds and stabilizes Nrdp1, augmenting its activity.
PMID:17145873
Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth.
  • Nrdp1 suppresses ErbB3 levels and ErbB2/ErbB3-driven proliferation, motility and downstream MAPK and PI3K/AKT signaling; loss of Nrdp1 enhances breast tumor growth.
PMID:18541373
Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress.
  • Nrdp1 ubiquitinates Parkin (poly-Ub chains in vitro and in cells), promoting its proteasome-dependent degradation, lowering Parkin activity and increasing ROS; Parkin abrogates Nrdp1-induced oxidative stress.
PMID:21516116
Next-generation sequencing to generate interactome datasets.
PMID:22493164
Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial complexity in human ubiquitination networks.
PMID:24056301
The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response.
  • Study of USP33 and the RAS-like GTPase RALB in autophagy and innate immunity; RNF41 is recorded as an interactor (source of the small GTPase binding annotation).
PMID:24105792
Protein microarray characterization of the S-nitrosoproteome.
PMID:25036637
A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:25910212
Widespread macromolecular interaction perturbations in human genetic disorders.
PMID:26496610
A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
PMID:27353365
The ER structural protein Rtn4A stabilizes and enhances signaling through the receptor tyrosine kinase ErbB3.
  • Nrdp1 binds and targets ErbB3/ErbB4 for degradation; the reticulon Rtn4A binds Nrdp1 via the core reticulon domain and sequesters it into ER tubules, suppressing Nrdp1 function and stabilizing ErbB3. Nrdp1 normally localizes to the cytosol/perinuclear region.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
Reactome:R-HSA-1358789
Self-ubiquitination of RNF41
Reactome:R-HSA-1358790
RNF41 ubiquitinates ERBB3
Reactome:R-HSA-1358792
RNF41 ubiquitinates activated ERBB3
Reactome:R-HSA-1358795
Deubiquitination of RNF41 by P-USP8
Reactome:R-HSA-1358797
Ubiquitinated RNF41 binds P-USP8
Reactome:R-HSA-1358798
RNF41 binds neuregulin-activated ERBB3
Reactome:R-HSA-1358801
ERBB3 binds RNF41 ubiquitin ligase

Suggested Questions for Experts

Q: How is RNF41 substrate choice (ErbB3/ErbB4 vs BRUCE vs Parkin vs MYD88/cytokine receptors) coordinated, and is it governed by localization (cytosol/perinuclear vs ER tubules), USP8 status, or stimulus?

Q: To what extent does the RNF41-PRKN pathway controlling autophagosome-lysosome fusion in late mitophagy depend on RNF41 catalytic activity versus scaffolding, and how does it relate to RNF41's pro-oxidant effect via Parkin degradation?

Suggested Experiments

Experiment: Perform quantitative ubiquitinome/proteome profiling in RNF41-knockout versus wild-type cells, with and without USP8 and Rtn4A perturbation, to define the endogenous RNF41 substrate repertoire and how localization controls substrate selection.

Experiment: Reconstitute RNF41-mediated ubiquitination in vitro with wild-type and RING-mutant (C34S/H36Q, D56V) RNF41 against ErbB3, BRUCE and Parkin with defined E2 panels to compare catalytic efficiency and chain types across substrates.

📚 Additional Documentation

Notes

(RNF41-notes.md)

RNF41 / NRDP1 / FLRF review notes

UniProt: Q9H4P4 (RNF41_HUMAN), 317 aa. EC 2.3.2.27. RING-type E3 ubiquitin-protein ligase.
Synonyms: NRDP1 (neuregulin receptor degradation protein-1), FLRF, RING finger protein 41.

Domain architecture

  • RING-type zinc finger 18..57 (degenerate; catalytic, engages E2). Catalytic residues
    Cys34/His36/Asp56 required for activity [UniProt MUTAGEN: C34S+H36Q loss of activity;
    D56V loss of activity].
  • SIAH-type zinc finger 78..138 (degenerate).
  • C-terminal substrate/USP8-binding domain (PDB 2FZP/2GWF, residues 193-317); dimerizes;
    binds substrate ErbB3 and the DUB USP8.
    PMID:27353365
  • Originally described as an RBCC/TRIM-like protein. PMID:11867753

Core molecular function

  • RING-type E3 ubiquitin-protein ligase / ubiquitin-protein transferase (EC 2.3.2.27).
    Genuine catalytic RING E3. [UniProt EC 2.3.2.27; CATALYTIC ACTIVITY E2~Ub -> substrate Lys]
  • Autoubiquitinated -> proteasomal degradation; stabilized by USP8 (deubiquitination).
    [PMID:15314180 "Nrdp1 protein undergoes efficient proteasome-dependent degradation and
    that mutations in its RING finger domain that disrupt ubiquitin ligase activity enhance
    stability"; "USP8 markedly enhanced the stability of Nrdp1"]
  • Zinc ion binding (RING + SIAH-type Zn finger) [UniProt KW Zinc-finger].

Substrates / processes (heart of RNF41 biology)

  • ErbB3 (and ErbB4) — Nrdp1 binds the receptor cytoplasmic tail (activation-independent) and
    mediates growth-factor-independent ubiquitination and proteasomal/ERAD degradation,
    maintaining steady-state ErbB3/ErbB4 levels; specific for ErbB3/ErbB4, NOT EGFR/ErbB2.
    Loss of Nrdp1 raises ErbB3 and enhances ErbB2/ErbB3 breast tumor growth, migration,
    MAPK and PI3K/AKT signaling.
    [PMID:11867753; PMID:27353365 "the E3 ubiquitin ligase Nrdp1...targets ErbB3 and ErbB4 for
    degradation"; PMID:17145873 "loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell
    growth"] Reactome: RNF41 ubiquitinates ERBB3 (R-HSA-1358790/1358792).
  • Rtn4A/Nogo-A sequesters Nrdp1 in ER tubules and suppresses its function, stabilizing
    ErbB3. Nrdp1 localizes to cytosol/perinuclear region and redistributes to ER tubules.
    PMID:27353365
  • BIRC6/BRUCE/Apollon — Nrdp1 binds and ubiquitinates the giant IAP BRUCE, promoting its
    proteasomal degradation and triggering apoptosis (extrinsic/intrinsic). USP8 stabilizes
    Nrdp1 which then induces apoptosis.
    PMID:14765125
  • PRKN/Parkin — Nrdp1 ubiquitinates Parkin (poly-Ub chains in vitro and in cells),
    accelerating its proteasomal degradation, reducing Parkin activity and increasing ROS;
    Parkin abrogates Nrdp1-induced oxidative stress. Relevant to Parkinson disease.
    [PMID:18541373 "Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on
    Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate";
    "overexpression of Nrdp1 increased the production of reactive oxygen species (ROS), which
    was abrogated by co-expression of Parkin"]
  • MYD88, TBK1 — Nrdp1 polyubiquitinates MYD88 (negatively regulating MyD88-dependent
    pro-inflammatory cytokines) and promotes TRIF-dependent type I IFN and TBK1/IRF3
    activation. [UniProt FUNCTION; PMID:19483718 (not cached)]
  • EPOR, IL3RA/CSF2RB — ubiquitination of erythropoietin and IL-3 receptors; controls
    hematopoietic progenitor differentiation (By similarity). [UniProt FUNCTION]
  • Mitophagy — RNF41-PRKN pathway regulates autophagosome-lysosome fusion during late
    mitophagy (with CLEC16A). [UniProt FUNCTION; PMID:24949970 (not cached)]

Subcellular location

  • Cytosol; perinuclear region; ER tubular network (with Rtn4A). [UniProt GO; PMID:27353365]

Annotation-call reasoning

  • ubiquitin protein ligase activity (GO:0061630) IDA/IEA, ubiquitin-protein transferase
    (GO:0004842) IDA/TAS — ACCEPT core MF; genuine RING E3.
  • protein polyubiquitination (GO:0000209) IDA/IEA — ACCEPT core BP.
  • protein autoubiquitination (GO:0051865) IDA — ACCEPT (well-supported; self-Ub regulates
    Nrdp1 levels). NOTE: GOA reference for this is PMID:24105792 (S-nitrosoproteome microarray)
  • keep but treat as non-core; the autoubiquitination biology itself is solid (PMID:15314180).
  • proteasomal protein catabolic process (GO:0010498) IDA — ACCEPT core BP (drives proteasomal
    degradation of ErbB3, BRUCE, Parkin).
  • positive regulation of protein catabolic process (GO:0045732) IMP — KEEP_AS_NON_CORE
    (Rtn4A/ErbB3 context; a regulatory framing).
  • receptor tyrosine kinase binding (GO:0030971) IPI — ACCEPT/KEEP: informative MF (ErbB3
    binding), substrate recognition. Keep as non-core supporting the ErbB3 substrate role.
  • erythropoietin receptor binding (GO:0005128) / interleukin-3 receptor binding (GO:0005135)
    IEA Ensembl (By similarity) — KEEP_AS_NON_CORE (ortholog-transferred substrate binding).
  • ER tubular network (GO:0071782) IBA/IDA, perinuclear region (GO:0048471) IDA, cytosol
    (GO:0005829) TAS — ACCEPT/KEEP localization (cytosol+perinuclear core; ER tubules is the
    Rtn4A-sequestered pool, real but non-core).
  • extrinsic apoptotic signaling pathway (GO:0097191) IDA — KEEP_AS_NON_CORE (BRUCE-degradation
    apoptosis role; downstream process).
  • 2000379/2000377 ROS metabolic process IMP — KEEP_AS_NON_CORE (Parkin-axis consequence).
  • 17145873 MGI annotations (neg reg cell proliferation, neg reg cell migration, reg MAPK
    cascade, reg PI3K/AKT) — KEEP_AS_NON_CORE (downstream of ErbB3 regulation; tumor context).
  • small GTPase binding (GO:0031267) IPI PMID:24056301 — the cited paper is about USP33/RALB;
    RNF41 appears as an interactor. UNDECIDED (cannot verify the specific RNF41-small GTPase
    binding from abstract). Per guardrails, do not REMOVE an IPI; mark UNDECIDED / keep cautious.
    Actually the GOA annotation is IPI to RNF41 enabling small GTPase binding from a screen;
    keep as KEEP_AS_NON_CORE bare-binding-like, or UNDECIDED. Use UNDECIDED.
  • enzyme binding (GO:0019899) IEA, protein domain specific binding (GO:0019904) IPI,
    identical protein binding (GO:0042802) IPI (dimerization is real), protein binding bare IPI
    — KEEP_AS_NON_CORE.

Pn Notes

(RNF41-pn-notes.md)

RNF41 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9H4P4
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-14
  • Batch change status: added

Source Files Checked

Deep Research Files

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

AIGR Review Snapshot

  • Description: RNF41 (RING finger protein 41; also known as NRDP1, neuregulin receptor degradation protein-1, and FLRF) is a 317-residue RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27). It has an N-terminal RING-type zinc finger (catalytic residues Cys34/His36/Asp56) that recruits a ubiquitin-charged E2 conjugating enzyme, a degenerate SIAH-type zinc finger, and a C-terminal dimerization/substrate-binding domain that engages substrates and the deubiquitinase USP8. RNF41 directs ubiquitination and, for several targets, proteasomal degradation of a defined substrate set. Its best-characterized substrates are the neuregulin receptor tyrosine kinases ErbB3 and ErbB4 (but not EGFR or ErbB2): RNF41 binds the ErbB3 cytoplasmic tail in an activation-independent manner and mediates growth-factor-independent ubiquitination and ER-associated/proteasomal degradation, thereby setting steady-state ErbB3/ErbB4 levels and restraining ErbB2/ErbB3-driven proliferative signaling and tumor growth. RNF41 also ubiquitinates and degrades the giant inhibitor-of-apoptosis protein BIRC6/BRUCE/Apollon, thereby promoting apoptosis, and ubiquitinates the E3 ligase PRKN/Parkin, accelerating its degradation, lowering Parkin activity and increasing reactive oxygen species (linking RNF41 to oxidative stress and Parkinson disease biology and to RNF41-PRKN regulation of late mitophagy). In innate immunity RNF41 polyubiquitinates MYD88 (limiting MyD88-dependent pro-inflammatory cytokines) and promotes TRIF-dependent type I interferon production and TBK1/IRF3 activation, and it ubiquitinates the erythropoietin and interleukin-3 receptors to control hematopoietic progenitor differentiation. RNF41 itself is regulated by autoubiquitination-driven proteasomal turnover that is counteracted by the deubiquitinase USP8 and by sequestration into endoplasmic-reticulum tubules by the reticulon Rtn4A/Nogo-A. It localizes mainly to the cytosol and perinuclear region, with a regulated pool on the ER tubular network.
  • Existing/core annotation action counts: ACCEPT: 20; KEEP_AS_NON_CORE: 32; UNDECIDED: 1

PN Consistency Summary

  • Consistency: Mostly consistent with a coverage gap. Deep research, review and PN agree RNF41 is a genuine catalytic RING E3 (Cys34/His36/Asp56; RING mutations abolish activity) degrading ErbB3/ErbB4, BRUCE/BIRC6 (→apoptosis) and Parkin/PRKN (→↑ROS). The PN row1 mitophagy story = "CLEC16A-RNF41-USP8 complex maintains mitochondrial function / late mitophagy; also ubiquitinates BIRC6 to upregulate autophagy" (tandfonline beta-cell paper). The review NOTES the RNF41-PRKN/CLEC16A late-mitophagy role in description and a suggested_question, but the cited beta-cell mitophagy paper is NOT in the review's references and there is NO mitophagy/autophagy BP annotation. So the PN's mitophagy assertion is mentioned but not evidenced or annotated in the review.
  • PN story / NEW pressure: Row1 projects GO:0000423 mitophagy as new_to_goa (verified real; confirmed ABSENT from GOA — RNF41 GOA has ligase MF/polyUb/proteasomal-catabolism but no mitophagy/autophagy BP). This is a candidate ADD but rests on the CLEC16A-RNF41-USP8 complex / late-mitophagy mechanism whose primary paper the review did not assess (UniProt cites PMID:24949970, not cached). Verify before adding. Row2 GO:0061630 = already_in_goa_exact — keep catalytic ligase MF as core (KEY PATTERN; RNF41 is unambiguously a catalytic RING E3, review ACCEPTs).
  • Evidence alignment: Divergent on the mitophagy arm. PN row1 ref (beta-cell ubiquitin-dependent mitophagy complex, tandfonline) is NOT in the review. Review's catalytic/substrate evidence (PMID:18541373 Parkin, PMID:14765125 BRUCE, PMID:11867753/27353365 ErbB3, PMID:15314180 USP8) is rich but covers the UPS/ligase side, not the mitophagy paper. PN row2 "19489725 / rev" is a family-review pointer.
  • Verdict: Consistent on catalytic ligase core (in GOA); the mitophagy ADD is plausible but the PN's primary mitophagy reference is absent from the review — verify before treating GO:0000423 as settled.

Full Consistency Review

  • UniProt: Q9H4P4 (NRDP1/FLRF) · batch: proteostasis-batch-2026-06-14 · review status: COMPLETE (very thorough; catalytic RING E3; ErbB3/ErbB4, BRUCE, Parkin substrates; mitophagy complex; 2 PN rows)
  • PN placement: row1 ALP|...|Marking substrates for selective autophagy|Mitophagy|PINK/PRKN pathway; row2 UPS|E3 ubiquitin and UBL ligases|RING|SIAH / SINA. PN-node mapping: row1 Mitophagy type→mapped GO:0000423 mitophagy (PINK/PRKN subtype no_mapping); row2 RING group→mapped GO:0061630 ubiquitin protein ligase activity (class context_only/too_broad).
  • Consistency: Mostly consistent with a coverage gap. Deep research, review and PN agree RNF41 is a genuine catalytic RING E3 (Cys34/His36/Asp56; RING mutations abolish activity) degrading ErbB3/ErbB4, BRUCE/BIRC6 (→apoptosis) and Parkin/PRKN (→↑ROS). The PN row1 mitophagy story = "CLEC16A-RNF41-USP8 complex maintains mitochondrial function / late mitophagy; also ubiquitinates BIRC6 to upregulate autophagy" (tandfonline beta-cell paper). The review NOTES the RNF41-PRKN/CLEC16A late-mitophagy role in description and a suggested_question, but the cited beta-cell mitophagy paper is NOT in the review's references and there is NO mitophagy/autophagy BP annotation. So the PN's mitophagy assertion is mentioned but not evidenced or annotated in the review.
  • PN story / NEW pressure: Row1 projects GO:0000423 mitophagy as new_to_goa (verified real; confirmed ABSENT from GOA — RNF41 GOA has ligase MF/polyUb/proteasomal-catabolism but no mitophagy/autophagy BP). This is a candidate ADD but rests on the CLEC16A-RNF41-USP8 complex / late-mitophagy mechanism whose primary paper the review did not assess (UniProt cites PMID:24949970, not cached). Verify before adding. Row2 GO:0061630 = already_in_goa_exact — keep catalytic ligase MF as core (KEY PATTERN; RNF41 is unambiguously a catalytic RING E3, review ACCEPTs).
  • Mapping strategy: Row2 catalytic-RING→GO:0061630 is correct (exact, in GOA, multiple IDA). Row1 mitophagy leaf→GO:0000423: defensible in principle (RNF41-PRKN-CLEC16A is a real mitophagy module) but the PINK/PRKN subtype is no_mapping and the propagation flows from the Mitophagy-type node; for RNF41 the role is regulatory/late-stage (autophagosome-lysosome fusion) rather than RNF41 being a cargo-marking receptor, so "Marking substrates for selective autophagy" placement is a slightly loose fit. Status mapped is acceptable if the late-mitophagy evidence is confirmed.
  • Evidence alignment: Divergent on the mitophagy arm. PN row1 ref (beta-cell ubiquitin-dependent mitophagy complex, tandfonline) is NOT in the review. Review's catalytic/substrate evidence (PMID:18541373 Parkin, PMID:14765125 BRUCE, PMID:11867753/27353365 ErbB3, PMID:15314180 USP8) is rich but covers the UPS/ligase side, not the mitophagy paper. PN row2 "19489725 / rev" is a family-review pointer.
  • Verdict: Consistent on catalytic ligase core (in GOA); the mitophagy ADD is plausible but the PN's primary mitophagy reference is absent from the review — verify before treating GO:0000423 as settled.
  • Recommended edits: [REF/WB] obtain/assess the PN-cited CLEC16A-RNF41-USP8 beta-cell mitophagy paper (and UniProt's PMID:24949970 late-mitophagy citation) — both absent from the review; they are the basis for GO:0000423. [YAML] if verified, add GO:0000423 mitophagy (regulation-of-mitophagy may fit better given RNF41's late/fusion-stage role) — currently the mitophagy role is mentioned in description but unannotated and uncited.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-14
  • review_yaml: genes/human/RNF41/RNF41-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | Mitophagy | PINK/PRKN pathway

  • UniProt: Q9H4P4
  • In branches: ALP, UPS
  • Notes: Important for mitophagy as part of CLEC16A-RNF41-USP8 complex. Also ubiquitinates BIRC6 to upregulate autophagy.
  • PN references (titles):
    • Full article: A ubiquitin-dependent mitophagy complex maintains mitochondrial function and insulin secretion in beta cells (tandfonline.com)
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy|PINK/PRKN pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0000423 mitophagy]
      rationale: The PN marking category for mitophagy captures upstream cargo-marking steps that commit mitochondrial substrates to the mitophagy pathway. That supports propagation to mitophagy.
    • [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 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | SIAH / SINA

  • UniProt: Q9H4P4
  • In branches: ALP, UPS
  • Signature domains: IPR001841
  • Auxiliary domains: IPR013010
  • PN references (titles):
    • 19489725 / rev
  • PN-node mapping records (path + ancestors):
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|SIAH / SINA
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

  • GO:0000423 mitophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

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

📄 View Raw YAML

 
id: Q9H4P4
gene_symbol: RNF41
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RNF41 (RING finger protein 41; also known as NRDP1, neuregulin receptor
  degradation protein-1, and FLRF) is a 317-residue RING-type E3
  ubiquitin-protein ligase (EC 2.3.2.27). It has an N-terminal RING-type zinc
  finger (catalytic residues Cys34/His36/Asp56) that recruits a ubiquitin-charged
  E2 conjugating enzyme, a degenerate SIAH-type zinc finger, and a C-terminal
  dimerization/substrate-binding domain that engages substrates and the
  deubiquitinase USP8. RNF41 directs ubiquitination and, for several targets,
  proteasomal degradation of a defined substrate set. Its best-characterized
  substrates are the neuregulin receptor tyrosine kinases ErbB3 and ErbB4 (but
  not EGFR or ErbB2): RNF41 binds the ErbB3 cytoplasmic tail in an
  activation-independent manner and mediates growth-factor-independent
  ubiquitination and ER-associated/proteasomal degradation, thereby setting
  steady-state ErbB3/ErbB4 levels and restraining ErbB2/ErbB3-driven
  proliferative signaling and tumor growth. RNF41 also ubiquitinates and degrades
  the giant inhibitor-of-apoptosis protein BIRC6/BRUCE/Apollon, thereby promoting
  apoptosis, and ubiquitinates the E3 ligase PRKN/Parkin, accelerating its
  degradation, lowering Parkin activity and increasing reactive oxygen species
  (linking RNF41 to oxidative stress and Parkinson disease biology and to
  RNF41-PRKN regulation of late mitophagy). In innate immunity RNF41
  polyubiquitinates MYD88 (limiting MyD88-dependent pro-inflammatory cytokines)
  and promotes TRIF-dependent type I interferon production and TBK1/IRF3
  activation, and it ubiquitinates the erythropoietin and interleukin-3 receptors
  to control hematopoietic progenitor differentiation. RNF41 itself is regulated
  by autoubiquitination-driven proteasomal turnover that is counteracted by the
  deubiquitinase USP8 and by sequestration into endoplasmic-reticulum tubules by
  the reticulon Rtn4A/Nogo-A. It localizes mainly to the cytosol and perinuclear
  region, with a regulated pool on the ER tubular network.
alternative_products:
- name: '1'
  id: Q9H4P4-1
- name: '2'
  id: Q9H4P4-2
  sequence_note: VSP_044670
existing_annotations:
- term:
    id: GO:0071782
    label: endoplasmic reticulum tubular network
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference that RNF41 acts on the ER tubular network. RNF41 ubiquitinates newly synthesized ErbB3 at the ER and can be sequestered into ER tubules by Rtn4A.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported localization (IDA in PMID:27353365) but represents the Rtn4A-sequestered/ER-associated degradation pool; the dominant active compartment is cytosolic/perinuclear.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of protein polyubiquitination, the core catalytic process of RNF41.
    action: ACCEPT
    reason: Core biological process directly demonstrated; RNF41 catalyzes polyubiquitin chain assembly on substrates including Parkin and BRUCE. Redundant with the IDA annotations.
    supported_by:
    - reference_id: PMID:18541373
      supporting_text: Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of zinc ion binding; RNF41 has a RING-type and a SIAH-type zinc finger that coordinate zinc.
    action: ACCEPT
    reason: Structurally required; the RING and SIAH-type zinc fingers coordinate zinc, essential for the RING fold and catalytic activity.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: ZN_FING         18..57
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic assignment of general protein ubiquitination, a parent of the specific polyubiquitination RNF41 catalyzes.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific protein polyubiquitination annotation (GO:0000209) better captures the role.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: ARBA machine-learning assignment of enzyme binding. RNF41 binds the deubiquitinase USP8 and the E3 ligase Parkin; a generic and uninformative binding term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic - RNF41 does bind enzymes (USP8, Parkin) - but enzyme binding is uninformative; more specific functional terms capture the biology.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: Interacts with USP8, ERBB3, PRKN and BIRC6
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of ubiquitin protein ligase activity, the core molecular function of RNF41 as a RING-type E3 ligase.
    action: ACCEPT
    reason: Core molecular function corroborated by direct experimental evidence (IDA); genuine catalytic RING E3 whose RING mutations abolish activity.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: High-throughput interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Chaperone interaction-network study interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: Interactome perturbation study interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Quantitative interactome (stoichiometry/abundance) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interactome-community study interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference-map interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Full=E3 ubiquitin-protein ligase NRDP1'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22493164
  qualifier: enables
  review:
    summary: Dimeric E3-RING interaction analysis; RNF41 self-associates (its C-terminal domain dimerizes, also forming trimers via the coiled-coil region). A real, informative homotypic interaction.
    action: KEEP_AS_NON_CORE
    reason: RNF41 genuinely self-associates (homodimer/oligomer), but this is a structural property supporting rather than defining its core ligase function.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome self-interaction (RNF41 homodimerization). A real homotypic interaction.
    action: KEEP_AS_NON_CORE
    reason: RNF41 self-associates; supports its function but is not the core catalytic role.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Interaction-perturbation study self-interaction (RNF41 homodimerization).
    action: KEEP_AS_NON_CORE
    reason: RNF41 self-associates; supports its function but is not the core catalytic role.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266'
- term:
    id: GO:0005128
    label: erythropoietin receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara) erythropoietin receptor binding; RNF41 ubiquitinates the EPO receptor to control hematopoietic progenitor differentiation (By similarity).
    action: KEEP_AS_NON_CORE
    reason: Reflects a real substrate-recognition interaction (EPOR) supporting the hematopoietic role, but is a specific non-core substrate transferred by similarity.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors
- term:
    id: GO:0005135
    label: interleukin-3 receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara) interleukin-3 receptor binding; RNF41 ubiquitinates the IL-3 receptor to control hematopoietic progenitor differentiation (By similarity).
    action: KEEP_AS_NON_CORE
    reason: Reflects a real substrate-recognition interaction (IL3RA/CSF2RB) supporting the hematopoietic role, but is a specific non-core substrate transferred by similarity.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358789
  qualifier: enables
  review:
    summary: Reactome curation (self-ubiquitination of RNF41) of ubiquitin-protein transferase activity, the core catalytic molecular function.
    action: ACCEPT
    reason: Core molecular function; RNF41 is a genuine catalytic RING E3 that transfers ubiquitin from E2 to substrate. Synonymous with ubiquitin protein ligase activity.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:27353365
  qualifier: enables
  review:
    summary: RNF41 binds the core reticulon domain of Rtn4A via its receptor-binding (C-terminal) domain; a specific domain-domain interaction.
    action: KEEP_AS_NON_CORE
    reason: Records a real, mechanistically relevant interaction (Rtn4A reticulon domain) that regulates RNF41 localization/activity, but is a binding term rather than RNF41's core function.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: the core reticulon domain is sufficient for mediating interaction with Nrdp1
- term:
    id: GO:0030971
    label: receptor tyrosine kinase binding
  evidence_type: IPI
  original_reference_id: PMID:27353365
  qualifier: enables
  review:
    summary: RNF41 binds the receptor tyrosine kinase ErbB3 (and ErbB4) via its C-terminal domain; the substrate-recognition interaction underlying ErbB3/ErbB4 degradation.
    action: KEEP_AS_NON_CORE
    reason: Informative substrate-recognition molecular function (ErbB3/ErbB4 binding) supporting the core ErbB3-degradation role; kept as non-core because the catalytic ligase activity is the defining function.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: The C-terminal domain of Nrdp1 is responsible for binding its substrate ErbB3
- term:
    id: GO:0045732
    label: positive regulation of protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:27353365
  qualifier: involved_in
  review:
    summary: RNF41 promotes proteasomal catabolism of ErbB3 (suppressed by Rtn4A). A regulatory framing of its degradative activity.
    action: KEEP_AS_NON_CORE
    reason: Correct but a higher-level regulatory term; the specific proteasomal protein catabolic process annotation better captures the role.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A counteracts the Nrdp1-mediated degradation of ErbB3
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:27353365
  qualifier: located_in
  review:
    summary: Direct localization of RNF41 to the cytosolic/perinuclear region (before Rtn4A-induced redistribution to ER tubules).
    action: ACCEPT
    reason: Experimentally supported core localization; RNF41 is normally cytosolic/perinuclear where it acts on its substrates.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0071782
    label: endoplasmic reticulum tubular network
  evidence_type: IDA
  original_reference_id: PMID:27353365
  qualifier: located_in
  review:
    summary: Direct evidence that RNF41 localizes to ER tubules upon Rtn4A expression; the Rtn4A-sequestered pool where RNF41 is held inactive.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but represents the Rtn4A-sequestered/ERAD pool rather than the dominant cytosolic/perinuclear active site.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A sequesters Nrdp1 in ER tubules where it cannot act on its substrates
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:18541373
  qualifier: enables
  review:
    summary: Direct evidence that RNF41 acts as a ubiquitin protein ligase, catalyzing poly-ubiquitin chains on Parkin in vitro and in cells. Core molecular function.
    action: ACCEPT
    reason: Core molecular function directly demonstrated; RNF41 is a genuine catalytic RING E3 ligase.
    supported_by:
    - reference_id: PMID:18541373
      supporting_text: Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IPI
  original_reference_id: PMID:24056301
  qualifier: enables
  review:
    summary: An interaction recorded in the USP33/RALB study; RNF41 appears as an interactor. The specific RNF41-small GTPase binding cannot be verified from the cached abstract, which concerns USP33 and the RAS-like GTPase RALB.
    action: UNDECIDED
    reason: Cannot verify the RNF41-specific small GTPase binding claim from available text (cached entry is abstract-only and centered on USP33/RALB). Per guidelines, an experimental IPI is not removed on the basis of incomplete cached evidence; defer to the curator.
    supported_by:
    - reference_id: PMID:24056301
      supporting_text: The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:18541373
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF41 catalyzes poly-ubiquitin chains on Parkin. Core biological process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; RNF41 assembles polyubiquitin chains on its substrate Parkin.
    supported_by:
    - reference_id: PMID:18541373
      supporting_text: Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
- term:
    id: GO:0010498
    label: proteasomal protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18541373
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF41 drives proteasome-dependent degradation of Parkin (and, in other studies, ErbB3 and BRUCE). Core biological process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; RNF41 targets substrates for proteasomal degradation.
    supported_by:
    - reference_id: PMID:18541373
      supporting_text: overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner
- term:
    id: GO:2000379
    label: positive regulation of reactive oxygen species metabolic process
  evidence_type: IMP
  original_reference_id: PMID:18541373
  qualifier: involved_in
  review:
    summary: Nrdp1 overexpression increases ROS production (abrogated by Parkin co-expression), via the RNF41-Parkin axis. A downstream consequence of degrading Parkin.
    action: KEEP_AS_NON_CORE
    reason: Real phenotype but a downstream consequence of RNF41-mediated Parkin degradation, not a core function.
    supported_by:
    - reference_id: PMID:18541373
      supporting_text: overexpression of Nrdp1 increased the production of reactive oxygen species (ROS), which was abrogated by co-expression of Parkin
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:24105792
  qualifier: enables
  review:
    summary: Protein-microarray (S-nitrosoproteome) detection of RNF41 ubiquitin-protein transferase activity. The catalytic molecular function is correct, though the source is a proteome-scale assay.
    action: ACCEPT
    reason: Core molecular function; consistent with the well-established catalytic RING E3 activity of RNF41, redundant with the IDA ligase-activity annotation.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:24105792
  qualifier: involved_in
  review:
    summary: RNF41 autoubiquitinates, leading to its own proteasomal degradation (counteracted by USP8). A well-established self-regulatory activity.
    action: ACCEPT
    reason: Well-supported activity (autoubiquitination regulates RNF41 levels; RING mutations that disrupt ligase activity stabilize RNF41); consistent with a genuine catalytic RING E3.
    supported_by:
    - reference_id: file:human/RNF41/RNF41-uniprot.txt
      supporting_text: 'Autoubiquitinated. Autoubiquitination leads to proteasomal degradation.'
- term:
    id: GO:0097191
    label: extrinsic apoptotic signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:14765125
  qualifier: involved_in
  review:
    summary: RNF41 ubiquitinates and degrades the IAP BRUCE/BIRC6, triggering apoptosis. A downstream process of its degradative activity.
    action: KEEP_AS_NON_CORE
    reason: Real apoptosis-promoting role via BRUCE degradation, but a downstream biological process rather than the core ligase function.
    supported_by:
    - reference_id: PMID:14765125
      supporting_text: Nrdp1 can be important in the initiation of apoptosis by catalyzing ubiquitination and degradation of BRUCE
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358789
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (self-ubiquitination of RNF41). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct core localization; RNF41 is predominantly cytosolic/perinuclear.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358790
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (RNF41 ubiquitinates ERBB3). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where RNF41 acts on its substrates.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358792
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (RNF41 ubiquitinates activated ERBB3). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where RNF41 acts on its substrates.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358795
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (deubiquitination of RNF41 by P-USP8). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where RNF41 acts on its substrates.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358797
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (ubiquitinated RNF41 binds P-USP8). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where RNF41 acts on its substrates.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358798
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (RNF41 binds neuregulin-activated ERBB3). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where RNF41 acts on its substrates.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358801
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (ERBB3 binds RNF41 ubiquitin ligase). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where RNF41 acts on its substrates.
    supported_by:
    - reference_id: PMID:27353365
      supporting_text: Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11867753
  qualifier: enables
  review:
    summary: Interaction with ErbB3 from the original Nrdp1/RBCC identification study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the foundational substrate interaction (ErbB3) but bare protein binding is uninformative; the receptor tyrosine kinase binding term is more specific.
    supported_by:
    - reference_id: PMID:11867753
      supporting_text: Nrdp1 interacts specifically with the neuregulin receptors ErbB3 and ErbB4
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:17145873
  qualifier: acts_upstream_of_or_within
  review:
    summary: Nrdp1 suppresses ErbB2/ErbB3-dependent breast tumor cell proliferation; loss of Nrdp1 enhances growth. A downstream consequence of ErbB3 degradation.
    action: KEEP_AS_NON_CORE
    reason: Real phenotype (tumor-suppressive) but downstream of RNF41-mediated ErbB3 degradation, not a core molecular function.
    supported_by:
    - reference_id: PMID:17145873
      supporting_text: overexpression of Nrdp1 in human breast cancer cells results in the suppression of ErbB3 levels, accompanied by the inhibition of cell growth and motility
- term:
    id: GO:0030336
    label: negative regulation of cell migration
  evidence_type: IMP
  original_reference_id: PMID:17145873
  qualifier: acts_upstream_of_or_within
  review:
    summary: Nrdp1 inhibits breast tumor cell motility/migration via ErbB3 suppression. A downstream consequence of ErbB3 degradation.
    action: KEEP_AS_NON_CORE
    reason: Real phenotype but downstream of RNF41-mediated ErbB3 degradation, not a core function.
    supported_by:
    - reference_id: PMID:17145873
      supporting_text: the inhibition of cell growth and motility and the attenuation of signal transduction pathways
- term:
    id: GO:0043408
    label: regulation of MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:17145873
  qualifier: acts_upstream_of_or_within
  review:
    summary: Nrdp1 attenuates ErbB3-driven MAPK signaling. A downstream consequence of ErbB3 degradation.
    action: KEEP_AS_NON_CORE
    reason: Real regulatory effect but downstream of RNF41-mediated ErbB3 degradation, not a core function.
    supported_by:
    - reference_id: PMID:17145873
      supporting_text: the attenuation of signal transduction pathways
- term:
    id: GO:0051896
    label: regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IDA
  original_reference_id: PMID:17145873
  qualifier: acts_upstream_of_or_within
  review:
    summary: Nrdp1 attenuates ErbB3-driven PI3K/AKT signaling. A downstream consequence of ErbB3 degradation.
    action: KEEP_AS_NON_CORE
    reason: Real regulatory effect but downstream of RNF41-mediated ErbB3 degradation, not a core function.
    supported_by:
    - reference_id: PMID:17145873
      supporting_text: the attenuation of signal transduction pathways
- term:
    id: GO:2000377
    label: regulation of reactive oxygen species metabolic process
  evidence_type: IMP
  original_reference_id: PMID:18541373
  qualifier: involved_in
  review:
    summary: RNF41 regulates ROS levels via the Parkin axis (knockdown lowers ROS). A downstream consequence of degrading Parkin.
    action: KEEP_AS_NON_CORE
    reason: Real phenotype but downstream of RNF41-mediated Parkin degradation; the more specific positive-regulation term also captures this.
    supported_by:
    - reference_id: PMID:18541373
      supporting_text: suppression of Nrdp1 by shRNA conferred SH-SY5Y cells a lower ROS level
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:18541373
  qualifier: enables
  review:
    summary: Direct evidence of RNF41 ubiquitin-protein transferase activity (catalyzing poly-Ub chains on Parkin). Core molecular function.
    action: ACCEPT
    reason: Core molecular function directly demonstrated; genuine catalytic RING E3.
    supported_by:
    - reference_id: PMID:18541373
      supporting_text: Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:14765125
  qualifier: involved_in
  review:
    summary: Direct evidence that RNF41 catalyzes ubiquitination of BRUCE/BIRC6. Core biological process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; RNF41 ubiquitinates the giant IAP BRUCE.
    supported_by:
    - reference_id: PMID:14765125
      supporting_text: purified Nrdp1 catalyzes BRUCE ubiquitination
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:14765125
  qualifier: enables
  review:
    summary: Direct evidence that purified RNF41 catalyzes BRUCE ubiquitination with an E2 (UbcH5c). Core molecular function.
    action: ACCEPT
    reason: Core molecular function directly demonstrated in a reconstituted assay; genuine catalytic RING E3.
    supported_by:
    - reference_id: PMID:14765125
      supporting_text: In the presence of an exogenous E2, UbcH5c, purified Nrdp1 catalyzes BRUCE ubiquitination
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14765125
  qualifier: enables
  review:
    summary: Interaction with BRUCE/BIRC6 (a substrate). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real substrate interaction (BRUCE) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:14765125
      supporting_text: Nrdp1 associates with BRUCE/apollon, a 530 kDa membrane-associated IAP
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15314180
  qualifier: enables
  review:
    summary: Interaction with the deubiquitinase USP8 (which stabilizes RNF41). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally important interaction (USP8) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:15314180
      supporting_text: we identified the deubiquitinating enzyme USP8 (also called Ubpy) as a protein that physically interacts with Nrdp1
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11867753
  title: An RBCC protein implicated in maintenance of steady-state neuregulin receptor
    levels.
  findings:
  - statement: Identifies Nrdp1/RNF41 as an RBCC RING ligase that binds the ErbB3/ErbB4 cytoplasmic tail (not EGFR/ErbB2) in an activation-independent manner and suppresses steady-state ErbB3/ErbB4 receptor levels.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; foundational identification of RNF41/Nrdp1 and its ErbB3/ErbB4 substrate specificity.
- id: PMID:14765125
  title: Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway
    for triggering apoptosis.
  findings:
  - statement: Nrdp1 binds and (with E2 UbcH5c) ubiquitinates the giant IAP BRUCE/BIRC6, promoting its proteasomal degradation and triggering apoptosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only in cache but the catalytic ubiquitination and apoptosis-promoting role are clearly established.
- id: PMID:15314180
  title: Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme
    USP8.
  findings:
  - statement: Nrdp1 undergoes RING-dependent autoubiquitination and proteasomal degradation; the deubiquitinase USP8 binds and stabilizes Nrdp1, augmenting its activity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes autoubiquitination/turnover and USP8-mediated stabilization.
- id: PMID:17145873
  title: Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth.
  findings:
  - statement: Nrdp1 suppresses ErbB3 levels and ErbB2/ErbB3-driven proliferation, motility and downstream MAPK and PI3K/AKT signaling; loss of Nrdp1 enhances breast tumor growth.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only in cache; supports the downstream tumor-suppressive/signaling phenotypes (MGI annotations).
- id: PMID:18541373
  title: Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress.
  findings:
  - statement: Nrdp1 ubiquitinates Parkin (poly-Ub chains in vitro and in cells), promoting its proteasome-dependent degradation, lowering Parkin activity and increasing ROS; Parkin abrogates Nrdp1-induced oxidative stress.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only in cache but provides clear IDA-grade support for catalytic activity, polyubiquitination, proteasomal degradation, and the ROS phenotype.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:22493164
  title: Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial
    complexity in human ubiquitination networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of the identical protein binding (RNF41 self-association) annotation; consistent with RNF41 dimerization.
- id: PMID:24056301
  title: The deubiquitylase USP33 discriminates between RALB functions in autophagy
    and innate immune response.
  findings:
  - statement: Study of USP33 and the RAS-like GTPase RALB in autophagy and innate immunity; RNF41 is recorded as an interactor (source of the small GTPase binding annotation).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Abstract-only and centered on USP33/RALB; the specific RNF41-small GTPase binding could not be verified from the cached text.
- id: PMID:24105792
  title: Protein microarray characterization of the S-nitrosoproteome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale (protein microarray) study; source of IDA transferase-activity and autoubiquitination annotations - catalytic function is correct though the assay is high-throughput.
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput chaperone interaction network; source of a bare protein binding annotation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of bare protein binding and identical protein binding annotations.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:27353365
  title: The ER structural protein Rtn4A stabilizes and enhances signaling through
    the receptor tyrosine kinase ErbB3.
  findings:
  - statement: Nrdp1 binds and targets ErbB3/ErbB4 for degradation; the reticulon Rtn4A binds Nrdp1 via the core reticulon domain and sequesters it into ER tubules, suppressing Nrdp1 function and stabilizing ErbB3. Nrdp1 normally localizes to the cytosol/perinuclear region.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; source of receptor tyrosine kinase binding, protein domain specific binding, perinuclear and ER tubular localization annotations.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of an identical protein binding (self-association) annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of a bare protein binding annotation.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Neurodegeneration interactome; source of a bare protein binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of a bare protein binding annotation.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of a bare protein binding annotation.
- id: Reactome:R-HSA-1358789
  title: Self-ubiquitination of RNF41
  findings: []
- id: Reactome:R-HSA-1358790
  title: RNF41 ubiquitinates ERBB3
  findings: []
- id: Reactome:R-HSA-1358792
  title: RNF41 ubiquitinates activated ERBB3
  findings: []
- id: Reactome:R-HSA-1358795
  title: Deubiquitination of RNF41 by P-USP8
  findings: []
- id: Reactome:R-HSA-1358797
  title: Ubiquitinated RNF41 binds P-USP8
  findings: []
- id: Reactome:R-HSA-1358798
  title: RNF41 binds neuregulin-activated ERBB3
  findings: []
- id: Reactome:R-HSA-1358801
  title: ERBB3 binds RNF41 ubiquitin ligase
  findings: []
core_functions:
- description: Functions as a catalytic RING-type E3 ubiquitin-protein ligase that recruits a ubiquitin-charged E2 conjugating enzyme via its N-terminal RING domain (Cys34/His36/Asp56) and transfers ubiquitin to substrate lysines, assembling polyubiquitin chains and directing proteasomal degradation of substrates; also autoubiquitinates to regulate its own levels.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18541373
    supporting_text: Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells
  - reference_id: PMID:14765125
    supporting_text: In the presence of an exogenous E2, UbcH5c, purified Nrdp1 catalyzes BRUCE ubiquitination
  directly_involved_in:
  - id: GO:0000209
    label: protein polyubiquitination
  - id: GO:0010498
    label: proteasomal protein catabolic process
- description: Sets steady-state levels of the neuregulin receptor tyrosine kinases ErbB3 and ErbB4 by binding their cytoplasmic tail and mediating growth-factor-independent ubiquitination and ER-associated/proteasomal degradation (specific for ErbB3/ErbB4, not EGFR/ErbB2), thereby restraining ErbB2/ErbB3-driven proliferative signaling.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0048471
    label: perinuclear region of cytoplasm
  supported_by:
  - reference_id: PMID:11867753
    supporting_text: Nrdp1 interacts specifically with the neuregulin receptors ErbB3 and ErbB4
  - reference_id: PMID:27353365
    supporting_text: The C-terminal domain of Nrdp1 is responsible for binding its substrate ErbB3
  directly_involved_in:
  - id: GO:0010498
    label: proteasomal protein catabolic process
- description: Ubiquitinates and degrades the giant inhibitor-of-apoptosis protein BIRC6/BRUCE to promote apoptosis, and ubiquitinates the E3 ligase PRKN/Parkin to accelerate its degradation, lowering Parkin activity and increasing reactive oxygen species.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:14765125
    supporting_text: Nrdp1 can be important in the initiation of apoptosis by catalyzing ubiquitination and degradation of BRUCE
  - reference_id: PMID:18541373
    supporting_text: overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner
  directly_involved_in:
  - id: GO:0000209
    label: protein polyubiquitination
proposed_new_terms: []
suggested_questions:
- question: How is RNF41 substrate choice (ErbB3/ErbB4 vs BRUCE vs Parkin vs MYD88/cytokine receptors) coordinated, and is it governed by localization (cytosol/perinuclear vs ER tubules), USP8 status, or stimulus?
- question: To what extent does the RNF41-PRKN pathway controlling autophagosome-lysosome fusion in late mitophagy depend on RNF41 catalytic activity versus scaffolding, and how does it relate to RNF41's pro-oxidant effect via Parkin degradation?
suggested_experiments:
- description: Perform quantitative ubiquitinome/proteome profiling in RNF41-knockout versus wild-type cells, with and without USP8 and Rtn4A perturbation, to define the endogenous RNF41 substrate repertoire and how localization controls substrate selection.
- description: Reconstitute RNF41-mediated ubiquitination in vitro with wild-type and RING-mutant (C34S/H36Q, D56V) RNF41 against ErbB3, BRUCE and Parkin with defined E2 panels to compare catalytic efficiency and chain types across substrates.