Affinage

RNF41

E3 ubiquitin-protein ligase NRDP1 · UniProt Q9H4P4

Length
317 aa
Mass
35.9 kDa
Annotated
2026-06-10
73 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF41 (Nrdp1/FLRF) is a RING finger E3 ubiquitin ligase that controls the abundance, surface display, and signaling output of a broad set of receptors and intracellular regulators through both degradative and non-degradative polyubiquitination (PMID:12411582, PMID:19483718). Its founding substrate is the receptor tyrosine kinase ErbB3/HER3, which it binds through a structurally defined C-terminal substrate-recognition domain and targets for proteasomal degradation via its RING domain (PMID:12411582, PMID:17384230, PMID:30523157). RNF41 activity is self-limiting: it undergoes RING-dependent autoubiquitination that drives its own turnover, and its coiled-coil domain mediates oligomerization required for efficient autoubiquitination in trans—a step functionally separable from substrate ubiquitination (PMID:15314180, PMID:24519943). RNF41 stability is set by a reciprocal relationship with the deubiquitinase USP8, which binds RNF41 through its rhodanese domain and stabilizes it, while RNF41 in turn ubiquitinates USP8 and remodels endosomal/ESCRT-0-associated trafficking of cytokine receptors (PMID:15314180, PMID:17035239, PMID:23750007). Through linkage-selective ubiquitination, RNF41 acts as a signaling switch rather than a simple degrader: it degrades MyD88 while activating TBK1 to bias TLR responses toward type I interferon, mediates K63 ubiquitination of C/EBPβ to drive M2 macrophage polarization, and applies K33-linked ubiquitin to ZAP70 to license Sts-phosphatase-mediated termination of TCR signaling (PMID:19483718, PMID:22707723, PMID:26390156). This ligase logic extends across receptor turnover, innate and adaptive immunity, apoptosis via BRUCE/Apollon degradation, autophagy/mitophagy through a CLEC16A–RNF41–USP8 complex and Parkin regulation, cell polarity, and cancer cell migration and metastasis (PMID:14765125, PMID:15632191, PMID:29180353, PMID:36822331, PMID:39112516). In prostate cancer, the androgen receptor transcriptionally upregulates RNF41 in a nuclear filamin A-dependent manner to drive ErbB3 degradation, an axis lost in castration-resistant disease (PMID:20587519, PMID:25759396).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2002 High

    Established RNF41 as a bona fide RING E3 ligase and defined its founding substrate, answering what enzymatic activity and target the protein has.

    Evidence Cell-free ubiquitination with E2 UbcH5, co-IP, and proteasome inhibitor degradation assays on ErbB3

    PMID:12411582

    Open questions at the time
    • Did not define linkage type of ErbB3 ubiquitin chains
    • Substrate-recognition surface not mapped structurally at this stage
  2. 2004 High

    Showed RNF41 controls its own abundance through autoubiquitination and is reciprocally stabilized by USP8, establishing the core regulatory loop governing ligase levels.

    Evidence Autoubiquitination/stability assays, reciprocal co-IP, and catalytic-dead USP8 mutagenesis; separately BRUCE/Apollon degradation by RNAi and apoptosis assays

    PMID:14765125 PMID:15314180

    Open questions at the time
    • Structural basis of RNF41–USP8 binding not yet resolved
    • How USP8 and autoubiquitination are dynamically balanced not defined
  3. 2005 High

    Extended the substrate repertoire to Parkin, showing RNF41 can regulate another E3 ligase and indirectly its downstream substrates.

    Evidence Y2H, in vitro binding, co-IP, co-localization, and pulse-chase half-life measurement

    PMID:15632191

    Open questions at the time
    • Physiological context of Parkin regulation not established in this study
    • Chain linkage on Parkin not characterized
  4. 2006 High

    Provided structural definition of the substrate-binding and USP8-interaction surfaces, explaining how RNF41 selects targets and partners.

    Evidence X-ray crystallography of the C-terminal domain and of the USP8 rhodanese–RNF41 complex, with mutagenesis

    PMID:17035239 PMID:17384230

    Open questions at the time
    • Full-length structure including RING and coiled-coil not solved
    • Predicted consensus binding motif across targets not experimentally validated for all substrates
  5. 2007 High

    Placed RNF41 in a regulated signaling cascade, showing ligand-driven kinase signaling tunes RNF41 stability and receptor turnover.

    Evidence siRNA, inhibitors, and USP8 T907 phospho-site mutagenesis defining a NRG1→Akt→USP8→Nrdp1→ErbB3 axis

    PMID:17210635

    Open questions at the time
    • Whether other ligands feed this axis not tested
    • Direct kinase–substrate stoichiometry not quantified
  6. 2008 Medium

    Broadened the receptor target set to hematopoietic cytokine receptors and linked RNF41 to differentiation and ROS, suggesting a general role in receptor homeostasis.

    Evidence Overexpression/knockdown in progenitor and SH-SY5Y cells, co-IP, colony assays, ROS measurement

    PMID:18495327 PMID:18541373

    Open questions at the time
    • Direct ubiquitination of IL-3R/EPOR/RARα not shown
    • ROS link to Parkin is correlative in cell overexpression
  7. 2009 High

    Revealed RNF41 as a signaling switch in innate immunity that degrades one effector while activating another, demonstrating non-degradative ubiquitination function in vivo.

    Evidence Reciprocal co-IP, in vivo ubiquitination, siRNA, and transgenic mouse LPS/VSV challenge for MyD88 and TBK1

    PMID:19483718

    Open questions at the time
    • Chain linkages distinguishing degradative vs activating outcomes not fully resolved here
    • Mechanism by which TBK1 ubiquitination promotes activation not detailed
  8. 2010 Medium

    Connected RNF41 to receptor trafficking decisions and to transcriptional control by the androgen receptor, linking ligase abundance to cancer-relevant receptor levels.

    Evidence Co-IP and protease inhibitor dissection of cytokine receptor cleavage/shedding; AR activation, promoter analysis, and xenografts for the AR–Nrdp1–ErbB3 axis

    PMID:20587519 PMID:21378310

    Open questions at the time
    • Direct mechanism coupling RNF41 to cathepsin-L vs ADAM activities unclear
    • How AR-driven RNF41 loss arises in castration resistance not mechanistically defined here
  9. 2012 High

    Demonstrated K63-linked, non-proteolytic ubiquitination as a means to enhance transcription factor activity, expanding RNF41's mechanistic repertoire.

    Evidence Co-IP, K63 ubiquitination assay, Arg1 reporter, and transgenic macrophage M2 polarization readouts on C/EBPβ

    PMID:22707723

    Open questions at the time
    • Site of C/EBPβ ubiquitination not mapped
    • How K63 chains enhance transcriptional activity mechanistically unresolved
  10. 2013 High

    Defined RNF41's role in ESCRT/endosomal trafficking and the regulated phosphorylation input controlling polarity, integrating ligase activity into membrane and cytoskeletal organization.

    Evidence Ubiquitination and RNAi epistasis on USP8/ESCRT-0 receptor trafficking; MARK2/Par-1b kinase assay and S254 mutagenesis for polarity

    PMID:23750007 PMID:24259665

    Open questions at the time
    • How S254 phosphorylation alters RNF41 activity biochemically not defined
    • Nature of 'RNF41 bodies' compartment not characterized
  11. 2014 High

    Showed coiled-coil-dependent oligomerization drives trans-autoubiquitination separable from substrate ubiquitination, clarifying how self-regulation and target turnover are mechanistically distinct.

    Evidence Cross-linking, SEC, native PAGE, domain deletion, and parallel ErbB3 vs auto-ubiquitination assays

    PMID:24519943

    Open questions at the time
    • Oligomer stoichiometry and architecture not structurally determined
    • Whether oligomerization influences substrate selectivity untested
  12. 2015 High

    Established a distinct K33 linkage coupling ubiquitination to phosphatase recruitment for TCR signal termination, and resolved the nuclear AR–filamin A requirement for RNF41 transcription.

    Evidence K33-specific ubiquitination, Nrdp1-knockout T cells, Sts1/2 dephosphorylation assays on ZAP70; ChIP and nuclear FLNA restoration for AR-driven transcription

    PMID:25759396 PMID:26390156

    Open questions at the time
    • How K33 chains physically recruit Sts phosphatases not structurally shown
    • Generality of K33 mechanism to other substrates unknown
  13. 2017 Medium

    Greatly expanded the substrate landscape to vesicle trafficking, kinetochore assembly, cell cycle, mitophagy, and PCP/migration, showing phosphorylation-gated substrate recognition.

    Evidence Co-IP, linkage-specific and phospho-dependent ubiquitination assays, MAPPIT screens, and functional readouts on VPS52, SGT1/PHLPP1, CLEC16A/USP8, CACYBP, and Dvl/VANGL

    PMID:28481871 PMID:28542518 PMID:28696259 PMID:29180353 PMID:31754404

    Open questions at the time
    • In vitro reconstitution lacking for several substrates
    • How phosphorylation switches substrate affinity not generalized across targets
  14. 2018 Medium

    Linked RNF41 to therapeutic receptor modulation and refined its interactome, positioning it as both a driver of anti-HER3 antibody efficacy and a node in clathrin-adaptor-dependent receptor signaling.

    Evidence shRNA screen with HER3 ubiquitination follow-up; multi-orthogonal interactome (AP-MS, BioID, Virotrap, MAPPIT, Y2H) and AP2S1 functional validation

    PMID:29560723 PMID:30523157

    Open questions at the time
    • Mechanism of acquired resistance via RNF41 loss not fully dissected
    • AP2S1 functional pathway downstream of RNF41 incompletely defined
  15. 2020 High

    Showed RNF41 ubiquitinates a receptor extracellular domain to gate ERAD versus cross-presentation, demonstrating context-dependent fate control of an immune receptor.

    Evidence Co-IP, extracellular-domain ubiquitination assay, and RNF41-knockout dendritic cell cross-presentation assays on Clec9A

    PMID:33264090

    Open questions at the time
    • How dead-cell uptake switches Clec9A interaction partners mechanistically unclear
    • Topology of extracellular-domain ubiquitination not structurally resolved
  16. 2021 Medium

    Embedded RNF41 in the A20 anti-inflammatory program and confirmed nuclear, catalytically active RNF41 bound to AR, refining its roles in immune signaling balance and prostate cancer.

    Evidence MS screens, co-IP, A20 ZnF4 mutagenesis with K48/K63 linkage assays; subcellular fractionation and AR hinge-region co-IP with ubiquitin assay

    PMID:34023381 PMID:34503235

    Open questions at the time
    • Nuclear RNF41 substrates not identified
    • Directionality of A20–RNF41 ubiquitin transfer not fully resolved
  17. 2023 Medium

    Mapped the intrinsically disordered region in CLEC16A as the RNF41 binding/destabilization site and established an in vivo requirement for RNF41 in autophagy-dependent spermiogenesis.

    Evidence NMR/CD with co-IP and degradation assays on the CLEC16A IDPR; Nrdp1-knockout mouse proteomics and sperm morphology analysis

    PMID:36822331 PMID:37759433

    Open questions at the time
    • How the tripartite complex balance is set in vivo not quantified
    • Causal contribution of individual substrates to infertility phenotype not isolated
  18. 2024 Medium

    Defined opposing pro- and anti-metastatic roles via non-canonical stabilizing ubiquitination of MYO1C and degradation of secreted Fam20C, showing RNF41 outputs are context- and substrate-specific.

    Evidence K27/K63-specific ubiquitination assays, endothelial-specific and tumor knockdown models, and in vivo bone/lung metastasis xenografts

    PMID:38654108 PMID:39112516

    Open questions at the time
    • How linkage choice (stabilizing vs degradative) is determined per substrate unresolved
    • Upstream signals selecting MYO1C vs Fam20C engagement unknown
  19. 2025 Medium

    Added NUDC as a degradative substrate linking RNF41 to microtubule dynamics and metastasis suppression, reinforcing its broad role in cytoskeletal and cancer cell behavior.

    Evidence Co-IP, ubiquitination assay, knockdown/overexpression, and tail-vein lung metastasis model

    PMID:40494872

    Open questions at the time
    • Chain linkage on NUDC not specified
    • In vitro reconstitution not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular code dictates RNF41's choice between degradative (K48) and non-degradative (K27/K33/K63) chain linkages on different substrates and how upstream signals select among its many targets.
  • No unifying rule linking substrate phosphorylation/context to chain-linkage output
  • No full-length structural model integrating RING, coiled-coil oligomerization, and substrate domain
  • Identity of nuclear RNF41 substrates undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 7 GO:0140096 catalytic activity, acting on a protein 6
Localization
GO:0005739 mitochondrion 2 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 3 R-HSA-5357801 Programmed Cell Death 1
Partners
CLEC16AERBB3MYD88PARK2TBK1USP8VPS52ZAP70
Complex memberships
CLEC16A-RNF41-USP8 mitophagy complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Nrdp1/FLRF is a RING finger-type E3 ubiquitin ligase that physically associates with ErbB3, ubiquitinates ErbB3 and itself in the presence of E2 enzyme UbcH5, and promotes proteasomal degradation of ErbB3. The RING finger domain is required for enhancing ErbB3 degradation, while the C-terminal half alone associates with ErbB3 and acts as a dominant-negative. Cell-free ubiquitination assay, co-immunoprecipitation, domain deletion/mutagenesis, proteasome inhibitor experiments Proceedings of the National Academy of Sciences of the United States of America High 12411582
2004 Nrdp1 associates with and ubiquitinates BRUCE/apollon (a 530 kDa IAP) in vitro (with E2 UbcH5c) and in vivo, promoting its proteasomal degradation. Apoptotic stimuli induce BRUCE degradation in a Nrdp1-dependent manner; RNAi knockdown of Nrdp1 reduces apoptosis-induced BRUCE loss. Overexpression of Nrdp1 or knockdown of BRUCE promotes apoptosis. In vitro ubiquitination assay, co-immunoprecipitation, RNA interference, overexpression apoptosis assays The EMBO journal High 14765125
2004 Nrdp1 undergoes efficient proteasome-dependent self-ubiquitination (autoubiquitination), and RING finger mutations that disrupt ligase activity enhance Nrdp1 stability. The deubiquitinating enzyme USP8 physically interacts with Nrdp1 via its rhodanese and catalytic domains, and USP8 markedly stabilizes Nrdp1; a catalytically dead USP8 mutant destabilizes endogenous Nrdp1. Affinity chromatography, co-immunoprecipitation, stability/pulse-chase analysis, point mutagenesis of USP8 catalytic residue Molecular and cellular biology High 15314180
2005 Nrdp1 physically interacts with Parkin (validated by in vitro binding, co-IP, and co-localization), ubiquitinates Parkin, and accelerates Parkin degradation (reducing half-life from ~5 h to ~2.5 h), thereby reducing Parkin activity and reversing Parkin-mediated degradation of its substrate CDCrel-1. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, immunofluorescence co-localization, pulse-chase experiment The Journal of biological chemistry High 15632191
2006 Crystal structure of the C-terminal domain of Nrdp1/FLRF was solved at 1.95 Å. This domain is sufficient to mediate ErbB3 binding. Site-directed mutagenesis mapped the ErbB3-binding surface to a region conserved from invertebrates to vertebrates, localizing the substrate-recognition site. X-ray crystallography, site-directed mutagenesis, ErbB3-binding and degradation assays in transfected cells Protein science : a publication of the Protein Society High 17384230
2006 Crystal structure of the USP8 rhodanese domain in complex with Nrdp1 reveals that Nrdp1 has a novel protein fold that interacts with a conserved peptide loop of the rhodanese domain; a consensus sequence of this loop is found in other Nrdp1 targets, suggesting a common interaction mode. The amino-terminal domain of USP8 forms a homodimer. X-ray crystallography, structural analysis of Nrdp1–USP8 rhodanese domain complex The Journal of biological chemistry High 17035239
2007 NRG1 (neuregulin-1) treatment stabilizes USP8 through Akt-mediated phosphorylation of USP8 Thr907, which in turn stabilizes Nrdp1. Nrdp1 and USP8 knockdown both suppress NRG1-induced ErbB3 ubiquitination and degradation, establishing a NRG1→Akt→USP8→Nrdp1→ErbB3 protein stability cascade. siRNA knockdown, pharmacological inhibitors, phosphorylation site mutagenesis (T907), ErbB3 ubiquitination/degradation assays Molecular and cellular biology High 17210635
2008 Nrdp1 (FLRF) overexpression in hematopoietic progenitor cells decreases steady-state levels of IL-3 receptor, EPO receptor, and RARα, and attenuates cytokine- and retinoic acid-induced erythroid/myeloid differentiation. Immunoprecipitation shows FLRF physically interacts with IL-3R, EPOR, and RARα in a ligand-independent manner. Overexpression in hematopoietic progenitor cell lines, immunoprecipitation, hematopoietic colony-forming assays, Western blot Experimental hematology Medium 18495327
2008 Nrdp1 ubiquitinates Parkin in vitro and in cells in a dosage-dependent, proteasome-dependent manner. Overexpression of Nrdp1 increases reactive oxygen species (ROS) production, which is abrogated by co-expression of Parkin; Nrdp1 shRNA knockdown reduces ROS levels. In vitro ubiquitination assay, overexpression/knockdown in SH-SY5Y cells, ROS measurement Neuroscience letters Medium 18541373
2009 Nrdp1 directly binds and polyubiquitinates MyD88 (leading to its proteasomal degradation) and TBK1 (leading to its activation, not degradation), thereby suppressing MyD88-dependent NF-κB/AP-1 activation while promoting TBK1/IRF3-dependent IFN-β production in TLR-triggered macrophages. Nrdp1 knockdown inhibits MyD88 degradation and TBK1/IRF3 activation. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, transgenic mouse model (LPS challenge, VSV infection) Nature immunology High 19483718
2010 RNF41 interacts with JAK2-associated cytokine receptor complexes (leptin receptor, LIF receptor, IL-6 receptor) and controls their surface levels dually: ectopic RNF41 blocks intracellular cathepsin-L-dependent receptor cleavage while enhancing ADAM metalloprotease-dependent ectodomain shedding. Co-immunoprecipitation, pharmacological inhibitors of cathepsin L and ADAMs, receptor surface/shedding assays Journal of cell science Medium 21378310
2010 Androgen receptor (AR) transcriptionally upregulates Nrdp1 in androgen-dependent prostate cancer cells; AR activation promotes ErbB3 degradation in a Nrdp1-dependent manner. In castration-resistant prostate cancer, this AR-Nrdp1 regulatory axis is lost, leading to constitutively suppressed Nrdp1 and elevated ErbB3. Androgen withdrawal/AR activation experiments, Nrdp1 promoter analysis, Western blot for ErbB3 and Nrdp1, mouse xenograft model Cancer research Medium 20587519
2012 Nrdp1 interacts with and mediates K63-linked polyubiquitination of the transcription factor C/EBPβ, which enhances C/EBPβ transcriptional activity and promotes M2 macrophage polarization (upregulation of Arg1 and other M2 markers) in response to IL-4. This represents a non-proteolytic ubiquitin-dependent pathway. Immunoprecipitation, K63-linked ubiquitination assay, reporter gene assay (Arg1 promoter), Nrdp1 knockdown/transgenic macrophages The Journal of biological chemistry High 22707723
2013 RNF41 ubiquitinates USP8 and reduces USP8 protein levels, redistributing USP8 from ESCRT-0-associated compartments to RNF41 bodies. Loss of USP8 destabilizes the ESCRT-0 complex and blocks lysosomal degradation of cytokine receptors while promoting their recycling. USP8 knockdown phenocopies RNF41 overexpression on leptin and LIF receptor trafficking. Immunoprecipitation, ubiquitination assays, USP8 siRNA knockdown, ESCRT-0 stability assays, receptor trafficking experiments Journal of cell science High 23750007
2013 Par-1b (MARK2) kinase binds to and phosphorylates RNF41 on serine 254. This phosphorylation is required for epithelial cells to localize laminin-111 receptors to their basolateral surfaces, to properly anchor to laminin-111, and to establish apical-basal polarity. Kinase assay, phosphorylation site mutagenesis (S254), co-immunoprecipitation, laminin receptor localization assays, polarity assays Journal of cell science Medium 24259665
2014 Nrdp1 self-associates into a stable oligomeric complex in cells via its coiled-coil domain. Deletion of the coiled-coil domain abolishes oligomerization but does not affect ErbB3 ubiquitination/degradation. The coiled-coil domain is required for efficient Nrdp1 autoubiquitination via a trans mechanism, demonstrating that autoubiquitination and substrate ubiquitination are functionally separable. Chemical cross-linking, size exclusion chromatography, native PAGE, co-immunoprecipitation, domain deletion mutagenesis, ubiquitination assays The Journal of biological chemistry High 24519943
2015 Nrdp1 mediates K33-linked polyubiquitination of Zap70, which promotes dephosphorylation of Zap70 by phosphatases Sts1 and Sts2, thereby terminating early TCR signaling in CD8+ T cells. Nrdp1 physically interacts with Zap70 and with Sts1/Sts2 and connects K33-linked ubiquitin modification to Sts-mediated dephosphorylation. Co-immunoprecipitation, K33-specific ubiquitination assay, Nrdp1-deficient mouse T cells, Zap70 phosphorylation assays, Sts1/Sts2 dephosphorylation assays Nature immunology High 26390156
2015 Nuclear filamin A (FLNA) is required for AR binding to the Nrdp1 androgen response element (ARE) and AR-mediated Nrdp1 transcription. Restoration of nuclear FLNA in castration-resistant prostate cancer cells re-establishes AR binding to the Nrdp1 promoter, increases Nrdp1 transcription and protein expression, and restores androgen responsiveness. ChIP assay, promoter ARE binding, nuclear FLNA restoration, qRT-PCR, Western blot Endocrine-related cancer Medium 25759396
2016 Lenalidomide promotes EpoR/RNF41 association and inhibits RNF41 auto-ubiquitination, leading to reduced EpoR ubiquitination and stabilization of EpoR at the cell surface. This effect is cereblon-independent. RNF41 overexpression reduces steady-state EpoR levels, and lenalidomide-induced EpoR upregulation is abrogated when cellular RNF41 is overexpressed. Co-immunoprecipitation, auto-ubiquitination assay, EpoR/RNF41 transfection, shRNA knockdown of CRBN, flow cytometry for EpoR surface levels Cancer research Medium 27197154
2017 Nrdp1 physically interacts with VANGL1 and VANGL2 (PCP pathway components) and mediates K63-linked polyubiquitination of the DEP domain of Dishevelled (Dvl). This ubiquitination impairs Dvl binding to phosphatidic acid, blocking Dvl recruitment to the plasma membrane upon Wnt/Fzd stimulation and thereby suppressing PCP signaling and GBM cell migration. Co-immunoprecipitation, K63 ubiquitination assay, Dvl-phosphatidic acid binding assay, siRNA knockdown, migration/invasion assays Oncogene Medium 28481871
2017 RNF41 interacts with VPS52 (a subunit of the GARP and EARP complexes) via coiled-coil domain interactions. RNF41 ubiquitinates VPS52 and relocates it away from VPS53 (another GARP/EARP subunit) towards RNF41 bodies, revealing a role for RNF41 in regulating intracellular vesicle trafficking machinery. Array MAPPIT protein-protein interaction screen, co-immunoprecipitation, ubiquitination assay, co-localization microscopy PloS one Medium 28542518
2017 RNF41 ubiquitinates SGT1 in a phosphorylation-dependent manner, promoting SGT1 degradation and causing defective kinetochore assembly. The phosphatase PHLPP1 dephosphorylates SGT1 at Ser-17, Ser-249, Ser-289, and Thr-233, preventing SGT1 association with RNF41 and thereby protecting it from degradation. Depletion of RNF41 or expression of non-phosphorylatable SGT1 rescues kinetochore defects caused by PHLPP1 loss. Co-immunoprecipitation, ubiquitination assay, phosphorylation site mutagenesis, PHLPP1/RNF41 knockdown, kinetochore assembly assays The Journal of biological chemistry Medium 28696259
2017 Clec16a, Nrdp1, and USP8 form a tripartite ubiquitin-dependent complex that regulates β-cell mitophagy. Clec16a is an E3 ligase that promotes nondegradative ubiquitin conjugates to stabilize the complex. RNF41/Nrdp1 is a component of this mitophagy regulatory complex in pancreatic β-cells and is required for mitochondrial quality control, oxygen consumption, and insulin secretion. Co-immunoprecipitation, ubiquitination assay, genetic knockdown/overexpression in β-cells, mitophagy flux assays, metabolic readouts Diabetes Medium 29180353
2018 RNF41 was identified as a driver of anti-HER3 antibody (IgG 95) anti-proliferative activity via shRNA library screen. RNF41 is responsible for HER3 ubiquitination and downregulation upon antibody treatment, and RNF41 downregulation itself is a mechanism for acquired resistance to anti-HER3 antibody treatment. shRNA library screen (ubiquitin proteasome system), HER3 ubiquitination assay, receptor internalization/degradation assay The Journal of biological chemistry Medium 30523157
2018 AP2S1 (a clathrin adaptor subunit) was identified as an RNF41 interaction partner by multi-orthogonal interactome screen. RNF41 stabilizes and relocates AP2S1, and AP2S1 plays a role in leptin and LIF receptor signaling downstream of RNF41. Affinity purification-mass spectrometry, BioID, Virotrap, microarray MAPPIT, Y2H, functional validation with AP2S1 knockdown/overexpression Journal of proteome research Medium 29560723
2019 RNF41 binds CACYBP via its C-terminal substrate-binding domain, ubiquitinates CACYBP, and promotes its degradation via both proteasome- and lysosome-dependent pathways. RNF41-mediated CACYBP degradation attenuates CACYBP-induced Ser10 phosphorylation and cytoplasmic retention of p27Kip1, thereby restricting cell cycle progression. Co-immunoprecipitation, ubiquitination assay, proteasome/lysosome inhibitor experiments, immunofluorescence for p27 localization, cell cycle assays Theranostics Medium 31754404
2020 RNF41 directly binds and ubiquitinates the extracellular domains of the dendritic cell receptor Clec9A. At steady-state, RNF41 ubiquitination of Clec9A facilitates interactions with ER-associated degradation proteins to control Clec9A levels; following dead cell uptake, Clec9A interactions shift to favor antigen cross-presentation. RNF41 is a negative regulator of Clec9A-mediated cross-presentation. Co-immunoprecipitation, ubiquitination assay targeting extracellular domain, RNF41 knockout dendritic cells, antigen cross-presentation assays eLife High 33264090
2021 A20 interacts with Nrdp1/RNF41 in LPS-stimulated cells. The ZnF4 domain of A20 is required for Nrdp1 polyubiquitination. A20 knockout decreases K48-linked ubiquitination of MyD88 (reducing its degradation) but increases K63-linked ubiquitination of TBK1. Combined A20 and Nrdp1 inhibition shows that A20/Nrdp1 interaction is important for A20 anti-inflammatory effects by modulating the balance between MyD88 degradation and TBK1 activation. Mass spectrometry screen, co-immunoprecipitation, A20 knockout, Nrdp1 knockdown, linkage-specific ubiquitination assays, domain mutagenesis (ZnF4), cytokine secretion assays The Journal of biological chemistry Medium 34023381
2021 NRDP1 is present in both cytoplasm and nucleus of prostate cancer cells. Its nuclear translocation is associated with androgen receptor (AR) activity; binding of NRDP1 to AR requires the AR hinge region. Nuclear NRDP1 retains ubiquitin ligase activity. Subcellular fractionation, immunohistochemistry, immunofluorescence with confocal microscopy, co-immunoprecipitation with AR constructs, HA-ubiquitin co-transfection assay Cancers Medium 34503235
2022 RNF41 promotes ubiquitination and degradation of ASB6 through direct interaction mediated by binding to FXR2 (which stabilizes RNF41 mRNA). Silencing RNF41 counteracts circFNDC3B-mediated suppression of colorectal cancer stemness and metastasis, placing RNF41-mediated ASB6 degradation downstream of the circFNDC3B-FXR2 axis. Co-immunoprecipitation, RNA immunoprecipitation, RNA pull-down, ubiquitination assay, siRNA knockdown, in vivo xenograft Cell death & disease Medium 36446779
2023 The CLEC16A internal intrinsically disordered protein region (IDPR) is the site where RNF41 binds and acts to destabilize CLEC16A, promoting its degradation and thereby controlling the reciprocal regulatory balance within the CLEC16A-RNF41-USP8 mitophagy complex. Loss of this IDPR also destabilizes the tripartite complex. NMR and CD spectroscopy (IDPR confirmation), co-immunoprecipitation, ubiquitination assays, deletion mutagenesis of IDPR The Journal of biological chemistry Medium 36822331
2023 Global deletion of Nrdp1 in mice leads to male infertility by disrupting autophagy-associated acrosome biogenesis and mitochondrial arrangement during spermiogenesis. Nrdp1 deletion increases Parkin levels but decreases SIP/CacyBP, Drp1, and Tim23 in sperm, inhibiting autophagy. This establishes a functional role for Nrdp1 in promoting autophagy during spermiogenesis via its known substrates. Nrdp1 knockout mouse, quantitative proteomics, autophagy flux assays, Western blot, sperm morphology analysis Cells Medium 37759433
2024 RNF41 induces K27- and K63-linked non-canonical polyubiquitination of MYO1C to enhance its stability, which promotes actin remodeling and prostate cancer bone metastasis. RNF41 silencing reduces MYO1C levels and suppresses metastasis in an intra-arterial bone metastasis xenograft model. Co-immunoprecipitation, K27/K63-specific ubiquitination assay, RNF41 silencing, in vitro migration/invasion assays, in vivo bone metastasis xenograft model Oncogene Medium 39112516
2024 VEGF activates CHIP, which triggers Nrdp1 degradation in vascular endothelial cells. Nrdp1 deficiency increases secretion of Fam20C (a secretory kinase), which induces degradation of extracellular matrix and disrupts vascular basement membrane integrity, thereby promoting tumor metastasis. Nrdp1 normally targets Fam20C for degradation to maintain vascular basement membrane integrity. Conditional Nrdp1 knockout mice (endothelial-specific), co-immunoprecipitation, ubiquitination assay, Fam20C secretion assay, in vivo lung metastasis model, VEGF treatment experiments Oncogene Medium 38654108
2025 RNF41 directly interacts with NUDC and ubiquitinates it to promote its proteasomal degradation. RNF41 loss leads to increased NUDC stability, which enhances β-tubulin polymerization and promotes bladder cancer lung metastasis. Co-immunoprecipitation, ubiquitination assay, RNF41 knockdown and overexpression, in vitro migration/invasion assays, tail vein lung metastasis model Cell death & disease Medium 40494872

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon. Nature immunology 271 19483718
2002 Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proceedings of the National Academy of Sciences of the United States of America 138 12411582
2006 Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). The Journal of biological chemistry 134 17035239
2004 Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8. Molecular and cellular biology 134 15314180
2004 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis. The EMBO journal 120 14765125
2007 Neuregulin-induced ErbB3 downregulation is mediated by a protein stability cascade involving the E3 ubiquitin ligase Nrdp1. Molecular and cellular biology 101 17210635
2015 K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation. Nature immunology 83 26390156
2006 Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth. Cancer research 75 17145873
2017 Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy. Diabetes 60 29180353
2011 RNF41 (Nrdp1) controls type 1 cytokine receptor degradation and ectodomain shedding. Journal of cell science 55 21378310
2010 Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells. Cancer research 51 20587519
2011 Cardiac-specific overexpression of E3 ligase Nrdp1 increases ischemia and reperfusion-induced cardiac injury. Basic research in cardiology 50 21312039
2017 Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination. Oncogene 49 28481871
2005 RING finger ubiquitin-protein isopeptide ligase Nrdp1/FLRF regulates parkin stability and activity. The Journal of biological chemistry 48 15632191
2013 Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing. Journal of cell science 44 23750007
2022 m6A-modified circFNDC3B inhibits colorectal cancer stemness and metastasis via RNF41-dependent ASB6 degradation. Cell death & disease 42 36446779
2011 Overexpression of Nrdp1 in the heart exacerbates doxorubicin-induced cardiac dysfunction in mice. PloS one 42 21738612
2012 The E3 ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp1) promotes M2 macrophage polarization by ubiquitinating and activating transcription factor CCAAT/enhancer-binding Protein β (C/EBPβ). The Journal of biological chemistry 36 22707723
2019 CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics 35 31754404
2023 RNF41 orchestrates macrophage-driven fibrosis resolution and hepatic regeneration. Science translational medicine 30 37437019
2008 E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors. Experimental hematology 30 18495327
2008 Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress. Neuroscience letters 27 18541373
2016 Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41. Cancer research 23 27197154
2019 Nrdp1 is involved in hippocampus apoptosis in cardiopulmonary bypass-induced cognitive dysfunction via the regulation of ErbB3 protein levels. International journal of molecular medicine 22 30720051
2013 Phosphorylation of the E3 ubiquitin ligase RNF41 by the kinase Par-1b is required for epithelial cell polarity. Journal of cell science 22 24259665
2010 Post-transcriptional mechanisms contribute to the suppression of the ErbB3 negative regulator protein Nrdp1 in mammary tumors. The Journal of biological chemistry 22 20628057
2021 A20/Nrdp1 interaction alters the inflammatory signaling profile by mediating K48- and K63-linked polyubiquitination of effectors MyD88 and TBK1. The Journal of biological chemistry 21 34023381
2020 MiRNA-494 enhances M1 macrophage polarization via Nrdp1 in ICH mice model. Journal of inflammation (London, England) 20 32351331
2015 Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer. Endocrine-related cancer 20 25759396
2015 Nrdp1-mediated ErbB3 degradation inhibits glioma cell migration and invasion by reducing cytoplasmic localization of p27(Kip1). Journal of neuro-oncology 20 26088461
2014 Characterization of E3 ubiquitin ligase neuregulin receptor degradation protein-1 (Nrdp1) in the large yellow croaker (Larimichthys crocea) and its immune responses to Cryptocaryon irritans. Gene 19 25447921
2020 RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells. eLife 18 33264090
2014 Oligomerization of the Nrdp1 E3 ubiquitin ligase is necessary for efficient autoubiquitination but not ErbB3 ubiquitination. The Journal of biological chemistry 18 24519943
2007 Structure-based mutagenesis of the substrate-recognition domain of Nrdp1/FLRF identifies the binding site for the receptor tyrosine kinase ErbB3. Protein science : a publication of the Protein Society 18 17384230
2017 Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein. Frontiers in cellular neuroscience 16 28979191
2015 MiR-497 promotes metastasis of colorectal cancer cells through Nrdp1 inhibition. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 25926384
2021 Genome-wide association study in the Taiwan Biobank identifies four novel genes for human height: NABP2, RASA2, RNF41 and SLC39A5. Human molecular genetics 15 34270706
2016 Hepatitis B virus X protein reduces the stability of Nrdp1 to up-regulate ErbB3 in hepatocellular carcinoma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 15 26846102
2017 RNF41 interacts with the VPS52 subunit of the GARP and EARP complexes. PloS one 13 28542518
2015 Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1-mediated ErbB3 ubiquitination and degradation. Journal of cellular and molecular medicine 13 26612725
2014 Nrdp1 inhibits growth of colorectal cancer cells by nuclear retention of p27. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 24867101
2015 Nrdp1 is Associated with Neuronal Apoptosis in Lipopolysaccharide-Induced Neuroinflammation. Neurochemical research 12 25896295
2014 Lower expression of Nrdp1 in human glioma contributes tumor progression by reducing apoptosis. IUBMB life 12 25355637
2020 Role of the Nrdp1 in Brain Injury Induced by Chronic Intermittent Hypoxia in Rats via Regulating the Protein Levels of ErbB3. Neurotoxicity research 10 32200526
2018 High-Confidence Interactome for RNF41 Built on Multiple Orthogonal Assays. Journal of proteome research 10 29560723
2017 Interplay between the phosphatase PHLPP1 and E3 ligase RNF41 stimulates proper kinetochore assembly via the outer-kinetochore protein SGT1. The Journal of biological chemistry 9 28696259
2015 The retinoic acid derivative, ABPN, inhibits pancreatic cancer through induction of Nrdp1. Carcinogenesis 9 26464195
2014 Nrdp1 inhibits metastasis of colorectal cancer cells by EGFR signaling-dependent MMP7 modulation. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 9 25330950
2011 Nrdp1 governs differentiation of the melanocyte lineage via Erbb3b signaling in the zebrafish embryogenesis. Biochemical and biophysical research communications 8 21596016
2024 A noncanonical E3 ubiquitin ligase RNF41-mediated MYO1C stability promotes prostate cancer metastasis by inducing actin remodeling. Oncogene 7 39112516
2018 Functional genomic characterization of a synthetic anti-HER3 antibody reveals a role for ubiquitination by RNF41 in the anti-proliferative response. The Journal of biological chemistry 7 30523157
2011 Suppression of Nrdp1 toxicity by Parkin in Drosophila models. Biochemical and biophysical research communications 7 22086177
2009 Genetic screening for mutations in the Nrdp1 gene in Parkinson disease patients in a Chinese population. Parkinsonism & related disorders 6 19800834
2024 VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane. Oncogene 5 38654108
2023 Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis. Cells 5 37759433
2015 Nrdp1 expression to predict clinical outcome and efficacy of adjuvant anthracyclines-based chemotherapy in breast cancer: A retrospective study. Cancer biomarkers : section A of Disease markers 5 25519010
2011 Overexpression of Nrdp1/FLRF sensitizes cells to oxidative stress. Biochemical and biophysical research communications 5 21693106
2024 Nrdp1-mediated Macrophage Phenotypic Regulation Promotes Functional Recovery in Mice with Mild Neurological Impairment after Intracerebral Hemorrhage. Neuroscience 4 38431041
2023 Reciprocal regulatory balance within the CLEC16A-RNF41 mitophagy complex depends on an intrinsically disordered protein region. The Journal of biological chemistry 4 36822331
2019 Nrdp1 increases neuron apoptosis via downregulation of Bruce following intracerebral haemorrhage. Journal of inflammation (London, England) 4 31827407
2018 Decreased RNF41 expression leads to insulin resistance in skeletal muscle of obese women. Metabolism: clinical and experimental 4 29410345
2016 Association between RNF41 gene c.-206 T > A genetic polymorphism and risk of congenital heart diseases in the Chinese Mongolian population. Genetics and molecular research : GMR 4 27323192
2016 Nrdp1-mediated degradation of BRUCE decreases cell viability and induces apoptosis in human 786-O renal cell carcinoma cells. Experimental and therapeutic medicine 3 27446249
2025 m6A-mediated silencing of RNF41 by METTL3/YTHDC1 disrupts autophagy to drive intervertebral disc degeneration. Cell biology and toxicology 2 41177830
2023 lncRNA LINC00960 promotes apoptosis by sponging ubiquitin ligase Nrdp1-targeting miR-183-5p. Acta biochimica et biophysica Sinica 2 36722261
2022 Mild Hypothermia Protects Brain Injury After Intracerebral Hemorrhage in Mice Via Enhancing the Nrdp1/MyD88 Signaling Pathway. Neurotoxicity research 2 36125699
2022 Deficiency of a novel lncRNA-HRAT protects against myocardial ischemia reperfusion injury by targeting miR-370-3p/RNF41 pathway. Frontiers in cardiovascular medicine 2 36172578
2021 Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes. Cancers 2 34503235
2025 Loss of RNF41 promotes bladder cancer metastasis through increasing NUDC stability to enhance tubulin polymerization. Cell death & disease 1 40494872
2020 Publisher Correction: K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation. Nature immunology 1 32034311
2020 Prediction of Ubiquitin Ligase Nrdp1-Associated Proteins in Glioma Database. Cell biochemistry and biophysics 1 32562142
2010 Apollon/RNF41 myocardial messenger RNA diagnoses cardiac allograft apoptosis in rejection. Transplantation 1 20098290
2026 Lung cancer cell-derived exosomal EHF drives M2 macrophage polarization via transcriptional activation of RNF41 to promote tumor progression. Regenerative therapy 0 41939996

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