{"gene":"ADRM1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2008,"finding":"ADRM1/Rpn13 is a proteasomal ubiquitin receptor that binds K48-linked diubiquitin (~90 nM affinity) through a conserved N-terminal pleckstrin-like receptor for ubiquitin (Pru) domain, and also binds UBL domains of UBL-UBA shuttle proteins; functional linkage with Rpn10 was established by synthetic lethality in yeast when both ubiquitin-binding sites are mutated.","method":"Biochemical binding assays, NMR, isothermal titration calorimetry, yeast genetics (double-mutant epistasis)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (ITC, NMR, in vitro binding, genetic epistasis), replicated across labs","pmids":["18497817"],"is_preprint":false},{"year":2006,"finding":"ADRM1 (hRpn13) recruits the deubiquitinating enzyme Uch37 to the 19S proteasome by binding Uch37's C-terminal tail; this binding relieves Uch37 autoinhibition and accelerates ubiquitin-AMC hydrolysis, but processing of polyubiquitin chains requires full 19S incorporation. ADRM1 is itself anchored to the S1/Rpn2 subunit of the 19S complex.","method":"Co-IP, mass spectrometry, in vitro DUB activity assay (ubiquitin-AMC), biochemical reconstitution of sub-complexes","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution of subcomplexes plus enzymatic assay, replicated by independent lab same year","pmids":["16906146"],"is_preprint":false},{"year":2006,"finding":"The C-terminal half of hRpn13/ADRM1 directly binds UCH37 and enhances its isopeptidase activity; knockdown of hRpn13 in 293T cells increases ubiquitin conjugates and decreases short-lived protein degradation, while overexpression or dominant-negative C-terminal fragment also reduces proteolysis and induces cell death.","method":"Affinity purification, co-IP, in vitro isopeptidase assay, siRNA knockdown, transfection/dominant-negative analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (pulldown, enzymatic assay, KD phenotype), consistent with PMID 16906146","pmids":["17139257"],"is_preprint":false},{"year":2006,"finding":"ADRM1 is a stoichiometric component of the 26S proteasome regulatory ATPase complex, present in cells in amounts equimolar with core 19S subunit S6a, with no detectable free pool; recombinant ADRM1 can bind to pre-existing 26S proteasomes in cell extracts.","method":"Co-immunoprecipitation, gel-filtration chromatography, native PAGE, Western blot quantification","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical methods establishing stoichiometric incorporation","pmids":["16815440"],"is_preprint":false},{"year":2013,"finding":"The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of RPN13/ADRM1 in the 19S regulatory particle, inhibiting proteasome function and triggering accumulation of polyubiquitinated proteins, ER stress-related apoptosis, and tumor growth inhibition in xenograft models.","method":"Covalent drug-protein adduct characterization, cell-based proteasome reporter assay, xenograft mouse models","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 — covalent binding characterized, functional consequence demonstrated in vitro and in vivo","pmids":["24332045"],"is_preprint":false},{"year":2014,"finding":"When proteolysis is inhibited in cells or purified 26S proteasomes, the proteasome-associated ubiquitin ligase Ube3c/Hul5 selectively poly-ubiquitinates Rpn13, strongly decreasing the proteasome's ability to bind and degrade ubiquitin-conjugated proteins (but not peptide substrates), acting as an autoinhibitory mechanism.","method":"In vitro ubiquitination assay with purified proteasomes, mass spectrometry, cell-based accumulation assay with various proteasome inhibitors","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution with purified components plus cell-based validation, multiple orthogonal methods","pmids":["24811749"],"is_preprint":false},{"year":2015,"finding":"The DEUBAD domain of RPN13 activates UCH-L5/Uch37 by positioning its C-terminal ULD domain and crossover loop to promote substrate binding and catalysis; crystal structures reveal that the related DEUBAD domain of INO80G inhibits UCH-L5 by exploiting the same structural elements but driving a radically different conformation that blocks ubiquitin docking via molecular mimicry.","method":"Crystal structure determination, biochemical activity assays, mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional mutagenesis validation","pmids":["25702870"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of hRpn13 Pru domain bound to a C-terminal segment of hRpn2 shows that a proline-rich hRpn2 extension stretches across the ubiquitin-binding canyon of the Pru domain, overlapping the RA190-binding surface; hRpn13 binds preferentially to hRpn2/proteasomes over RA190; RA190 directly binds and inactivates Uch37 in addition to targeting hRpn13.","method":"X-ray crystallography, SPR biophysics, NMR, cell-based assays, ADRM1 deletion in HCT116 cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with biophysical and cell-based validation","pmids":["28598414"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of the RPN13 PRU domain with RPN2 C-terminal peptide and with ubiquitin reveal that both bind the same PRU domain surface; the C-terminal 14 residues of RPN2 constitute the primary RPN13-docking epitope on the proteasome; ubiquitin, RPN2, and UCH37 bind RPN13 with independent energetics.","method":"X-ray crystallography, surface plasmon resonance, fluorescence polarization, mutational analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with quantitative binding measurements and mutagenesis","pmids":["28442575"],"is_preprint":false},{"year":2014,"finding":"Rpn13 activates Uch37 by disrupting Uch37 oligomeric autoinhibition: full-length Uch37 forms oligomers where catalytic domains block each other's ubiquitin-binding site; the C-terminal domain of Rpn13 (residues 270–407) sequesters Uch37 monomers into a 1:1 complex with 12-fold higher activity, as demonstrated by mutagenesis, NMR, SAXS, and FRET.","method":"Mutagenesis, NMR, SAXS, FRET, in vitro DUB activity assay (Ub-AMC)","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 1 — multiple structural and biochemical methods in one study","pmids":["24752541"],"is_preprint":false},{"year":2019,"finding":"NMR structure of Rpn13 Pru domain with K48-diubiquitin shows bivalent interaction: proximal Ub binds similarly to monoubiquitin, while distal Ub contacts a largely electrostatic surface of Rpn13; a charge-reversal mutation weakening distal Ub binding causes accumulation of ubiquitinated proteins in cells, establishing the structural basis for Rpn13 K48-chain linkage selectivity.","method":"NMR structure determination, single-molecule FRET, mutagenesis, cell-based ubiquitin conjugate accumulation assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with smFRET confirmation and functional mutagenesis","pmids":["30962947"],"is_preprint":false},{"year":2020,"finding":"NMR structure of hRpn13 Pru:hRpn2(940-953):K48-diubiquitin reveals that hRpn2-bound hRpn13 selects a dynamic, extended conformation of K48-diubiquitin distinct from the closed crystallographic conformation; hRpn13 exchanges between the two ubiquitins within 100 ms but prefers the proximal ubiquitin via interactions with the K48 linker region.","method":"NMR structure determination, NMR dynamics experiments","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with dynamics characterization","pmids":["32160516"],"is_preprint":false},{"year":2010,"finding":"Rpn13 is required for iNOS interaction with UCH37 and for iNOS degradation; IκB-α is also a substrate for the Rpn13/UCH37 complex, linking the Rpn13 pathway to NF-κB activation.","method":"siRNA knockdown, co-IP, degradation assays in cells","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — cell-based KD with specific substrate readouts, single lab","pmids":["20634424"],"is_preprint":false},{"year":2014,"finding":"The double-capped 26S proteasome is structurally asymmetric: while both 19S particles contain Rpn10/S5a, only one of the two 19S caps contains Rpn13, as demonstrated by AQUA mass spectrometry and biochemical fractionation in both yeast and mammals.","method":"AQUA-MS quantification, biochemical fractionation, validated in yeast and mammals","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — unbiased quantitative MS with cross-species validation","pmids":["24429290"],"is_preprint":false},{"year":2015,"finding":"Rpn13 is the major proteasomal receptor for the E3 ubiquitin ligase parkin: the N-terminal Ubl domain of parkin binds directly to the Pru domain of Rpn13 with >10-fold higher affinity than ubiquitin; Rpn13 knockdown increases parkin levels, abrogates parkin recruitment to the proteasome, delays clearance of mitochondrial proteins during mitophagy, and enhances parkin autoubiquitination.","method":"NMR, mutational analysis, Co-IP, siRNA knockdown, affinity measurements, cell-based mitophagy assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — NMR mapping + reciprocal Co-IP + KD phenotype, multiple orthogonal methods","pmids":["25666615"],"is_preprint":false},{"year":2015,"finding":"Rpn13 and Rpn10 function as redundant ubiquitin receptors in the mammalian liver: simultaneous liver-specific knockout of both causes severe liver injury and massive accumulation of ubiquitin conjugates, and mHR23B and ubiquilin/Plic-1/4 shuttle proteins fail to bind the proteasome only when both receptors are absent.","method":"Conditional double-knockout mice (liver-specific), co-IP, Western blot for ubiquitin conjugates, rescue experiments","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean double KO with defined phenotype and rescue, validated in mouse","pmids":["26222436"],"is_preprint":false},{"year":2014,"finding":"SUMOylation of proteasomal scaffolding protein Psmd1/RPN2 at a lysine immediately adjacent to its Adrm1-binding domain, catalyzed by PIASy, regulates the association of Adrm1 with Psmd1; the SUMO deconjugating enzyme xSENP1 interacts with Psmd1 and its disruption delays mitotic exit.","method":"Xenopus egg extract system, SUMO site mapping, co-IP, cell-based mitotic exit assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — SUMOylation site mapped with functional consequence on Adrm1 binding, single lab","pmids":["24910440"],"is_preprint":false},{"year":2015,"finding":"The C-terminal region of Rpn13 binds the TPR domain of SGTA (cochaperone for mislocalised membrane proteins); SGTA overexpression increases mislocalised membrane protein levels in a manner dependent on its interaction with Rpn13, suggesting SGTA can regulate substrate access to the proteasome via Rpn13.","method":"Co-IP, pulldown, SGTA/Rpn13 mutational analysis, cell-based substrate degradation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct binding and functional KD/OE assay, single lab","pmids":["26169395"],"is_preprint":false},{"year":2016,"finding":"SGTA interacts with the proteasomal ubiquitin receptor Rpn13 through a carboxylate clamp mechanism involving the TPR domain of SGTA and a defined region of the Rpn13 C-terminal domain; structural and biophysical characterization confirmed this interface mediates Rpn13-SGTA association in cells.","method":"Structural and biophysical characterization (ITC, NMR, X-ray), mutagenesis, cell-based co-IP","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — structural characterization with mutagenesis and cellular validation","pmids":["27827410"],"is_preprint":false},{"year":2010,"finding":"In mice, Rpn13 deletion produces tissue-specific effects on proteasomal function (increased activity in adrenal gland and lymphoid organs, decreased in testes and brain), infertility due to defective gametogenesis, and elevated serum growth hormone/FSH, while Uch37 deletion causes prenatal lethality with severe embryonic brain defects.","method":"Whole-body knockout mice, proteasome activity assays in tissues, hormone measurements, histology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined tissue-specific phenotypes, single lab","pmids":["21048919"],"is_preprint":false},{"year":2019,"finding":"Phosphorylation of RPN2 Tyr-950 by Jurkat cell kinase(s) enhances RPN13 binding affinity; a 1.76-Å crystal structure of the RPN2-RPN13 pTyr-950-ubiquitin complex reveals specific interactions with positively charged RPN13 residues that explain affinity increase without conformational change.","method":"X-ray crystallography, mutagenesis, quantitative binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and quantitative binding, single lab","pmids":["31064842"],"is_preprint":false},{"year":2015,"finding":"A 38-amino acid peptide from the C-terminus of hRpn2/PSMD1 binds the hRpn13 Pru domain with 12 nM affinity and displaces endogenous Rpn13 from the proteasome in 293T cells; overexpression of this peptide leads to accumulation of ubiquitinated proteins.","method":"NMR epitope mapping, fluorescence polarization binding assay, co-IP, cell-based ubiquitin conjugate assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 — NMR mapping plus quantitative affinity measurement and cell-based validation","pmids":["26466095"],"is_preprint":false},{"year":2010,"finding":"Phospho-ΔNp63α binds to the RPN13 promoter (via a TP63-responsive element, in association with DDIT3/CHOP, NF-Y, NF-κB) to activate RPN13 gene transcription in response to cisplatin; this leads to NOS2/iNOS degradation, and RPN13 knockdown rescues NOS2 from cisplatin-dependent inactivation.","method":"ChIP, promoter-reporter assay, siRNA knockdown, protein degradation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP and functional knockdown, single lab","pmids":["20959455"],"is_preprint":false},{"year":2018,"finding":"HDAC8 physically interacts with the proteasome receptor ADRM1; inhibition of HDAC8 decreases MGMT protein levels in glioblastoma cells, and this regulation is disrupted by temozolomide specifically in TMZ-sensitive cells, suggesting that the HDAC8-ADRM1 interaction regulates MGMT levels independently of promoter methylation.","method":"Co-IP (HDAC8-ADRM1 interaction), HDAC8 inhibitor/shRNA, Western blot for MGMT","journal":"Genes & cancer","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with pharmacological/shRNA follow-up, mechanism not fully reconstituted","pmids":["31798765"],"is_preprint":false},{"year":2009,"finding":"Adrm1 interacts with Atp6v0d2 (V-ATPase V0 domain d2 subunit) as identified by yeast two-hybrid and confirmed by co-immunoprecipitation in vivo; Adrm1 is required for osteoclast cell migration and maturation.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown in osteoclast differentiation assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — yeast two-hybrid confirmed by single Co-IP, limited mechanistic follow-up","pmids":["19818731"],"is_preprint":false},{"year":2016,"finding":"RPN13/ADRM1 Pru domain functions as a proteasomal receptor for MHC class I antigen processing: both Rpn10 and Rpn13 regulate processing of the NY-ESO-1 cancer/testis antigen and supply of HLA-A*0201-restricted peptides, with non-lysine ubiquitination sites governing this process.","method":"siRNA knockdown of Rpn13/Rpn10, antigen presentation assay, ubiquitination site mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — genetic KD with specific antigen-presentation readout, single lab","pmids":["26903513"],"is_preprint":false},{"year":2023,"finding":"ADRM1/Rpn13 acts as a resection inhibitor in DNA end processing; during DNA double-strand break repair, ADRM1 is removed from the CDW19S complex (a proteasome variant decorated with CRL4WDR70 ubiquitin ligase) by CRL4WDR70-catalyzed ubiquitination, permitting MRE11 and EXO1 nuclease-mediated resection; HBx stabilizes ADRM1, imposing a resection barrier and causing viral homologous recombination deficiency.","method":"Co-IP, chromatin fractionation, knockdown/knockout, in vitro and cell-based resection assays, xenograft models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical and cell-based methods identifying novel non-proteasomal function, single lab","pmids":["37815873"],"is_preprint":false},{"year":2023,"finding":"ADRM1/Rpn13 upregulates UCH37 expression and activates its deubiquitination activity; activated UCH37 then deubiquitinates ALK5 to stabilize it, maintaining extracellular matrix homeostasis in articular cartilage; global ADRM1 KO accelerates cartilage degeneration in a DMM mouse model.","method":"Knockout mice, overexpression in vivo, in vitro deubiquitination assay, co-IP (ADRM1-UCH37), Western blot for ALK5 ubiquitination","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo KO phenotype plus mechanistic biochemistry, single lab","pmids":["37406898"],"is_preprint":false},{"year":2025,"finding":"A novel splice variant of ADRM1 lacking exon 9 (ADRM1-ΔEx9) interacts with deubiquitinase BAP1 (instead of UCH37) via its shortened C-terminus, altering proteasome specificity; the exon 8-10 fusion creates a de novo binding site for tumor suppressor FBXW7, leading to its selective proteasome-mediated degradation and promoting hepatocellular carcinoma.","method":"SMRT sequencing, human organoids, hydrodynamic in vivo transfection mouse model, Proteome Profiler Ubiquitin Array, co-IP (ADRM1-ΔEx9-BAP1, ADRM1-ΔEx9-FBXW7), patient-derived xenografts","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — novel splice variant with multiple experimental systems, single lab","pmids":["39788431"],"is_preprint":false},{"year":2025,"finding":"Protea-Tac, a heterobifunctional degrader using ADRM1/Rpn13 as the proteasome-targeting moiety fused to a target-specific intracellular antibody, integrates into 26S proteasomes without altering their integrity and degrades substrates (c-Fos, BRD4, tau, TDP43, GFP-ODC) in a ubiquitin-independent manner via direct proteasomal targeting.","method":"Reconstitution of chimeric degrader in cells, proteasome structural/functional integrity assays, in vivo xenograft mouse model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — modular system with multiple substrates and in vivo validation, but preprint","pmids":[],"is_preprint":true}],"current_model":"ADRM1/hRpn13 is a stoichiometric 19S proteasome subunit that docks onto the C-terminus of RPN2/PSMD1 (a phosphorylatable interaction modulated by SUMOylation of RPN2) via its N-terminal Pru domain, which simultaneously serves as the ubiquitin receptor preferentially recognizing K48-linked polyubiquitin chains through bivalent contacts with both proximal and distal ubiquitin moieties; its C-terminal DEUBAD domain recruits and allosterically activates the deubiquitinating enzyme UCH37/UCHL5 by disrupting UCH37 autoinhibitory oligomerization, coupling ubiquitin chain recognition with distal-end chain disassembly at the proteasome; one of the two 19S caps in double-capped 26S proteasomes contains Rpn13, creating structural asymmetry; Rpn13 is also autoubiquitinated by proteasome-associated Ube3c/Hul5 under proteotoxic stress, reducing ubiquitin-conjugate binding as a feedback mechanism; and in addition to its canonical proteasomal role, ADRM1 participates in DNA double-strand break resection control, MHC class I antigen processing, parkin recruitment to the proteasome, and selective substrate degradation including iNOS, IκB-α, and ALK5 via the Rpn13/UCH37 axis."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing ADRM1 as a bona fide stoichiometric proteasome subunit answered whether it was a transient interactor or an integral 19S component, and revealed it as the anchor for deubiquitinase UCH37.","evidence":"Co-IP, native PAGE, gel filtration, and in vitro DUB assays in reconstituted subcomplexes and human cells","pmids":["16815440","16906146","17139257"],"confidence":"High","gaps":["How ADRM1 is incorporated during proteasome assembly was not addressed","Whether ADRM1 directly binds ubiquitin was unknown at this stage"]},{"year":2008,"claim":"Identifying ADRM1 as a direct ubiquitin receptor via its Pru domain resolved how ubiquitinated substrates are recognized at the proteasome beyond RPN10, and genetic epistasis in yeast established functional redundancy between the two receptors.","evidence":"ITC, NMR, and yeast double-mutant synthetic lethality","pmids":["18497817"],"confidence":"High","gaps":["Structural basis for polyubiquitin chain linkage selectivity was not yet determined","How Pru domain simultaneously accommodates RPN2 docking and ubiquitin binding was unclear"]},{"year":2010,"claim":"Mouse knockout studies revealed that Rpn13 loss produces tissue-specific rather than globally lethal phenotypes (unlike UCH37 deletion), establishing that Rpn13 is dispensable for viability but critical for gametogenesis and specific tissues.","evidence":"Whole-body Rpn13 and Uch37 knockout mice with tissue proteasome activity profiling","pmids":["21048919"],"confidence":"Medium","gaps":["Why certain tissues (testes, brain) are selectively vulnerable to Rpn13 loss is unexplained","Compensatory mechanisms by RPN10 or shuttle receptors in surviving tissues were not dissected"]},{"year":2010,"claim":"Linking the Rpn13/UCH37 axis to specific substrate degradation (iNOS, IκB-α) and to transcriptional regulation of RPN13 by ΔNp63α established that the receptor can direct selective proteolysis with pathway-level consequences for NF-κB signaling.","evidence":"siRNA knockdown, co-IP, ChIP on RPN13 promoter, substrate degradation assays","pmids":["20634424","20959455"],"confidence":"Medium","gaps":["Whether Rpn13/UCH37 selectivity for iNOS/IκB-α reflects direct substrate recognition or indirect effects was not resolved","Generality of transcriptional regulation of RPN13 expression beyond the cisplatin/ΔNp63α axis is unknown"]},{"year":2014,"claim":"Demonstration that only one of two 19S caps in double-capped 26S proteasomes contains Rpn13 established intrinsic structural asymmetry, raising the possibility that the two caps have distinct substrate-processing capabilities.","evidence":"AQUA mass spectrometry and biochemical fractionation in yeast and mammals","pmids":["24429290"],"confidence":"High","gaps":["Functional consequences of this asymmetry for substrate selection and processing are unknown","What determines which cap receives Rpn13 is not established"]},{"year":2014,"claim":"Discovery of Rpn13 autoubiquitination by proteasome-associated Ube3c under proteotoxic stress revealed a feedback mechanism that reduces the proteasome's ability to capture new ubiquitinated substrates when proteolysis is impaired.","evidence":"In vitro ubiquitination with purified proteasomes, mass spectrometry, proteasome inhibitor treatments in cells","pmids":["24811749"],"confidence":"High","gaps":["How autoubiquitinated Rpn13 is subsequently resolved (deubiquitinated or degraded) is unclear","Whether this feedback operates physiologically outside of inhibitor treatment is not demonstrated"]},{"year":2014,"claim":"Structural and biophysical dissection of how Rpn13 disrupts UCH37 autoinhibitory oligomers into active 1:1 complexes resolved the allosteric activation mechanism, explaining how deubiquitination is spatially coupled to substrate recognition.","evidence":"Mutagenesis, NMR, SAXS, FRET, and in vitro DUB assays","pmids":["24752541"],"confidence":"High","gaps":["How the Rpn13–UCH37 complex coordinates with other proteasomal DUBs (Rpn11/USP14) during substrate processing was not addressed"]},{"year":2015,"claim":"Crystal structures of the DEUBAD–UCH37 complex revealed the molecular basis for Rpn13-mediated activation versus INO80G-mediated inhibition of the same enzyme, establishing a paradigm of DEUBAD-domain molecular mimicry.","evidence":"Crystal structures with mutagenesis and activity assays","pmids":["25702870"],"confidence":"High","gaps":["How the switch between activating (Rpn13) and inhibiting (INO80G) DEUBAD contexts is regulated in vivo is not known"]},{"year":2015,"claim":"In vivo double-knockout of Rpn13 and Rpn10 in mouse liver proved their functional redundancy as the essential proteasomal ubiquitin receptors and showed that UBL-UBA shuttle proteins require at least one intrinsic receptor for proteasome docking.","evidence":"Liver-specific conditional double-knockout mice with co-IP and rescue experiments","pmids":["26222436"],"confidence":"High","gaps":["Whether other tissues exhibit the same strict redundancy or have additional compensatory mechanisms is untested","Individual contribution of each receptor to specific substrate classes in vivo is unresolved"]},{"year":2015,"claim":"Identification of Rpn13 as the major proteasomal receptor for the E3 ligase parkin, with its Ubl domain binding the Pru domain at higher affinity than ubiquitin, connected Rpn13 to mitophagy and Parkinson's disease-relevant biology.","evidence":"NMR, quantitative binding assays, reciprocal co-IP, siRNA, and cell-based mitophagy assay","pmids":["25666615"],"confidence":"High","gaps":["Whether Rpn13-dependent parkin recruitment is relevant in dopaminergic neurons in vivo is untested","Competition between parkin-Ubl and ubiquitin for the Pru domain under physiological conditions is not quantified"]},{"year":2017,"claim":"Crystal structures of the Pru–RPN2 and Pru–ubiquitin interfaces resolved the overlapping binding surfaces, explaining how Rpn13 integrates proteasome docking with ubiquitin recognition and clarifying how RA190 targets this interface.","evidence":"X-ray crystallography, SPR, NMR, mutagenesis in HCT116 ADRM1-deleted cells","pmids":["28598414","28442575"],"confidence":"High","gaps":["How Rpn13 simultaneously engages RPN2 and ubiquitin on a shared surface in the context of the intact proteasome is structurally unresolved at full 26S resolution"]},{"year":2019,"claim":"NMR structure of the Pru–K48-diubiquitin complex revealed bivalent chain recognition through distinct proximal and distal ubiquitin contacts, providing the structural basis for K48-linkage selectivity; RPN2 Tyr-950 phosphorylation was shown to enhance Rpn13 binding, adding a layer of post-translational regulation.","evidence":"NMR structures, smFRET, charge-reversal mutagenesis with cellular validation; crystal structure of pTyr-950–RPN2–Rpn13–Ub","pmids":["30962947","31064842"],"confidence":"High","gaps":["The kinase(s) responsible for RPN2 Tyr-950 phosphorylation in vivo and its regulation are not identified","How bivalent K48-diUb binding transitions to chain handoff to UCH37 or Rpn11 is mechanistically unclear"]},{"year":2023,"claim":"Discovery of ADRM1 as a resection inhibitor in DNA double-strand break repair, removed by CRL4-WDR70 ubiquitination to permit MRE11/EXO1 activity, established a non-proteasomal function for ADRM1 in genome integrity.","evidence":"Co-IP, chromatin fractionation, knockout, in vitro and cell-based resection assays, xenograft models","pmids":["37815873"],"confidence":"Medium","gaps":["The mechanism by which ADRM1 physically blocks resection is not structurally defined","Whether this function is independent of UCH37 and proteasome catalytic activity is not fully dissected","Confirmation by independent laboratories is needed"]},{"year":2025,"claim":"Identification of a cancer-associated splice variant (ADRM1-ΔEx9) that switches partner binding from UCH37 to BAP1 and creates a neo-binding site for FBXW7, directing its proteasomal degradation, revealed how alternative splicing can reprogram Rpn13 substrate specificity to promote hepatocellular carcinoma.","evidence":"SMRT sequencing, human organoids, hydrodynamic transfection mouse models, co-IP, patient-derived xenografts","pmids":["39788431"],"confidence":"Medium","gaps":["Prevalence and regulation of the ΔEx9 splice variant across cancer types is not characterized","Structural basis for BAP1 binding by the shortened C-terminus is not determined","Independent replication is needed"]},{"year":null,"claim":"Key unresolved questions include how Rpn13 coordinates with other proteasomal deubiquitinases (Rpn11, USP14) during processive substrate degradation, what determines asymmetric Rpn13 occupancy on double-capped proteasomes, and the in vivo physiological relevance of the Rpn13 autoubiquitination feedback loop.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-resolution cryo-EM structure of Rpn13-engaged substrate processing intermediate exists","In vivo dynamics of Rpn13 autoubiquitination and its reversal are unmeasured","Tissue-specific proteasome composition incorporating Rpn13 splice variants has not been systematically profiled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,14,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,6,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,13]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,3,5,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[26]}],"complexes":["26S proteasome 19S regulatory particle"],"partners":["UCHL5","PSMD1","PSMD4","PRKN","SGTA","UBE3C"],"other_free_text":[]},"mechanistic_narrative":"ADRM1 (hRpn13) is a stoichiometric 19S proteasome subunit that functions as a ubiquitin receptor and scaffold for deubiquitination at the proteasome, coupling substrate recognition to ubiquitin chain processing. Its N-terminal Pru domain docks onto the C-terminus of RPN2/PSMD1 and simultaneously recognizes K48-linked polyubiquitin chains through bivalent contacts with proximal and distal ubiquitin moieties, while its C-terminal DEUBAD domain recruits and allosterically activates UCH37/UCHL5 by disrupting UCH37 autoinhibitory oligomerization [PMID:18497817, PMID:16906146, PMID:25702870, PMID:24752541, PMID:30962947]. ADRM1 functions redundantly with RPN10 as proteasomal ubiquitin receptors; simultaneous loss of both in mouse liver causes massive ubiquitin-conjugate accumulation and organ failure, and its autoubiquitination by proteasome-associated Ube3c under proteotoxic stress serves as a feedback mechanism to reduce substrate engagement [PMID:26222436, PMID:24811749]. Beyond canonical proteasomal proteolysis, ADRM1 participates in MHC class I antigen processing, parkin recruitment during mitophagy, and DNA double-strand break resection control, where its CRL4-WDR70-mediated removal from a proteasome variant permits MRE11/EXO1 nuclease activity [PMID:26903513, PMID:25666615, PMID:37815873]."},"prefetch_data":{"uniprot":{"accession":"Q16186","full_name":"Proteasomal ubiquitin receptor ADRM1","aliases":["110 kDa cell membrane glycoprotein","Gp110","Adhesion-regulating molecule 1","ARM-1","Proteasome regulatory particle non-ATPase 13","hRpn13","Rpn13 homolog"],"length_aa":407,"mass_kda":42.2,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins (PubMed:16815440, PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:18497817, PubMed:24752541, PubMed:25702870, PubMed:25702872). This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required (PubMed:16815440, PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:18497817, PubMed:24752541, PubMed:25702870, PubMed:25702872). Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:16815440, PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:18497817, PubMed:24752541, PubMed:25702870, PubMed:25702872). Within the complex, functions as a proteasomal ubiquitin receptor (PubMed:18497817). Engages and activates 19S-associated deubiquitinases UCHL5 and PSMD14 during protein degradation (PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:24752541). UCHL5 reversibly associate with the 19S regulatory particle whereas PSMD14 is an intrinsic subunit of the proteasome lid subcomplex (PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:24752541)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16186/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADRM1","classification":"Not Classified","n_dependent_lines":513,"n_total_lines":1208,"dependency_fraction":0.4246688741721854},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMC4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/ADRM1","total_profiled":1310},"omim":[{"mim_id":"617842","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 1; PSMD1","url":"https://www.omim.org/entry/617842"},{"mim_id":"610650","title":"ADHESION-REGULATING MOLECULE 1; ADRM1","url":"https://www.omim.org/entry/610650"},{"mim_id":"601648","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 4; PSMD4","url":"https://www.omim.org/entry/601648"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20959455","citation_count":8,"is_preprint":false},{"pmid":"33645522","id":"PMC_33645522","title":"[Changes in the mitochondrial subproteome of mouse brain Rpn13-binding proteins induced by the neurotoxin MPTP and the neuroprotector isatin].","date":"2021","source":"Biomeditsinskaia khimiia","url":"https://pubmed.ncbi.nlm.nih.gov/33645522","citation_count":8,"is_preprint":false},{"pmid":"37714498","id":"PMC_37714498","title":"Discovery of a non-covalent ligand for Rpn-13, a therapeutic target for hematological cancers.","date":"2023","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/37714498","citation_count":7,"is_preprint":false},{"pmid":"37815873","id":"PMC_37815873","title":"Hepatitis B virus infection disrupts homologous recombination in hepatocellular carcinoma by stabilizing resection inhibitor ADRM1.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37815873","citation_count":5,"is_preprint":false},{"pmid":"30280096","id":"PMC_30280096","title":"Ubiquitin Receptor RPN13 Mediates the Inhibitory Interaction of Diphenyldihaloketones CLEFMA and EF24 With the 26S Proteasome.","date":"2018","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30280096","citation_count":4,"is_preprint":false},{"pmid":"37406898","id":"PMC_37406898","title":"ADRM1/RPN13 attenuates cartilage extracellular matrix degradation via enhancing UCH37-mediated ALK5 deubiquitination.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37406898","citation_count":4,"is_preprint":false},{"pmid":"1612770","id":"PMC_1612770","title":"Characterization of GP110, a neutrophil surface protein.","date":"1992","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/1612770","citation_count":4,"is_preprint":false},{"pmid":"37315065","id":"PMC_37315065","title":"Development and anticancer properties of Up284, a spirocyclic candidate ADRM1/RPN13 inhibitor.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37315065","citation_count":3,"is_preprint":false},{"pmid":"39788431","id":"PMC_39788431","title":"Spliced exon9 ADRM1 promotes liver oncogenicity via selective degradation of tumor suppressor FBXW7.","date":"2025","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/39788431","citation_count":3,"is_preprint":false},{"pmid":"2183624","id":"PMC_2183624","title":"Immunohistochemical analysis of the A4 and AO10 (gp110) cell-surface antigens of human astrocytoma.","date":"1990","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2183624","citation_count":3,"is_preprint":false},{"pmid":"38990850","id":"PMC_38990850","title":"Preclinical studies of RA475, a guanidine-substituted spirocyclic candidate RPN13/ADRM1 inhibitor for treatment of ovarian cancer.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38990850","citation_count":1,"is_preprint":false},{"pmid":"39519207","id":"PMC_39519207","title":"The Structural Role of RPN10 in the 26S Proteasome and an RPN2-Binding Residue on RPN13 Are Functionally Important in Arabidopsis.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39519207","citation_count":1,"is_preprint":false},{"pmid":"41406707","id":"PMC_41406707","title":"Comprehensive analysis and experimental confirmation identify ADRM1 plays an oncogenic and immunosuppression role in KIRC.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41406707","citation_count":0,"is_preprint":false},{"pmid":"39959199","id":"PMC_39959199","title":"Effects of ADRM1 on osteoblast differentiation and mineralization in osteoporosis.","date":"2025","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/39959199","citation_count":0,"is_preprint":false},{"pmid":"41018284","id":"PMC_41018284","title":"IGF2BP1-Mediates m6A Modification of KLF4 and Upregulates ADRM1 to Affect EndMT in Diabetic Atherosclerosis.","date":"2025","source":"Acta Cardiologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/41018284","citation_count":0,"is_preprint":false},{"pmid":"40422199","id":"PMC_40422199","title":"Non-Redundant Essential Roles of Proteasomal Ubiquitin Receptors Rpn10 and Rpn13 in Germ Cell Formation and Fertility.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/40422199","citation_count":0,"is_preprint":false},{"pmid":"40192613","id":"PMC_40192613","title":"Ubiquitin Receptor RPN13-Mediated \"Candidatus Liberibacter asiaticus\" Virulence Effector Degradation to Positively Regulate Immunity.","date":"2025","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40192613","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.18.670774","title":"Ubiquitin Receptor-Induced Proximity is Sufficient for Ubiquitin-Independent Targeted Protein Degradation via the 26S Proteasome","date":"2025-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670774","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.31.667872","title":"Structures of dynamic interactors at native proteasomes by PhIX-MS and cryoelectron microscopy","date":"2025-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.31.667872","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.30.610524","title":"Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways","date":"2024-09-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.30.610524","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48754,"output_tokens":7149,"usd":0.126748},"stage2":{"model":"claude-opus-4-6","input_tokens":10874,"output_tokens":3758,"usd":0.22248},"total_usd":0.349228,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"ADRM1/Rpn13 is a proteasomal ubiquitin receptor that binds K48-linked diubiquitin (~90 nM affinity) through a conserved N-terminal pleckstrin-like receptor for ubiquitin (Pru) domain, and also binds UBL domains of UBL-UBA shuttle proteins; functional linkage with Rpn10 was established by synthetic lethality in yeast when both ubiquitin-binding sites are mutated.\",\n      \"method\": \"Biochemical binding assays, NMR, isothermal titration calorimetry, yeast genetics (double-mutant epistasis)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (ITC, NMR, in vitro binding, genetic epistasis), replicated across labs\",\n      \"pmids\": [\"18497817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADRM1 (hRpn13) recruits the deubiquitinating enzyme Uch37 to the 19S proteasome by binding Uch37's C-terminal tail; this binding relieves Uch37 autoinhibition and accelerates ubiquitin-AMC hydrolysis, but processing of polyubiquitin chains requires full 19S incorporation. ADRM1 is itself anchored to the S1/Rpn2 subunit of the 19S complex.\",\n      \"method\": \"Co-IP, mass spectrometry, in vitro DUB activity assay (ubiquitin-AMC), biochemical reconstitution of sub-complexes\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution of subcomplexes plus enzymatic assay, replicated by independent lab same year\",\n      \"pmids\": [\"16906146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-terminal half of hRpn13/ADRM1 directly binds UCH37 and enhances its isopeptidase activity; knockdown of hRpn13 in 293T cells increases ubiquitin conjugates and decreases short-lived protein degradation, while overexpression or dominant-negative C-terminal fragment also reduces proteolysis and induces cell death.\",\n      \"method\": \"Affinity purification, co-IP, in vitro isopeptidase assay, siRNA knockdown, transfection/dominant-negative analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (pulldown, enzymatic assay, KD phenotype), consistent with PMID 16906146\",\n      \"pmids\": [\"17139257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADRM1 is a stoichiometric component of the 26S proteasome regulatory ATPase complex, present in cells in amounts equimolar with core 19S subunit S6a, with no detectable free pool; recombinant ADRM1 can bind to pre-existing 26S proteasomes in cell extracts.\",\n      \"method\": \"Co-immunoprecipitation, gel-filtration chromatography, native PAGE, Western blot quantification\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods establishing stoichiometric incorporation\",\n      \"pmids\": [\"16815440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of RPN13/ADRM1 in the 19S regulatory particle, inhibiting proteasome function and triggering accumulation of polyubiquitinated proteins, ER stress-related apoptosis, and tumor growth inhibition in xenograft models.\",\n      \"method\": \"Covalent drug-protein adduct characterization, cell-based proteasome reporter assay, xenograft mouse models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — covalent binding characterized, functional consequence demonstrated in vitro and in vivo\",\n      \"pmids\": [\"24332045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"When proteolysis is inhibited in cells or purified 26S proteasomes, the proteasome-associated ubiquitin ligase Ube3c/Hul5 selectively poly-ubiquitinates Rpn13, strongly decreasing the proteasome's ability to bind and degrade ubiquitin-conjugated proteins (but not peptide substrates), acting as an autoinhibitory mechanism.\",\n      \"method\": \"In vitro ubiquitination assay with purified proteasomes, mass spectrometry, cell-based accumulation assay with various proteasome inhibitors\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution with purified components plus cell-based validation, multiple orthogonal methods\",\n      \"pmids\": [\"24811749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The DEUBAD domain of RPN13 activates UCH-L5/Uch37 by positioning its C-terminal ULD domain and crossover loop to promote substrate binding and catalysis; crystal structures reveal that the related DEUBAD domain of INO80G inhibits UCH-L5 by exploiting the same structural elements but driving a radically different conformation that blocks ubiquitin docking via molecular mimicry.\",\n      \"method\": \"Crystal structure determination, biochemical activity assays, mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional mutagenesis validation\",\n      \"pmids\": [\"25702870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of hRpn13 Pru domain bound to a C-terminal segment of hRpn2 shows that a proline-rich hRpn2 extension stretches across the ubiquitin-binding canyon of the Pru domain, overlapping the RA190-binding surface; hRpn13 binds preferentially to hRpn2/proteasomes over RA190; RA190 directly binds and inactivates Uch37 in addition to targeting hRpn13.\",\n      \"method\": \"X-ray crystallography, SPR biophysics, NMR, cell-based assays, ADRM1 deletion in HCT116 cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with biophysical and cell-based validation\",\n      \"pmids\": [\"28598414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of the RPN13 PRU domain with RPN2 C-terminal peptide and with ubiquitin reveal that both bind the same PRU domain surface; the C-terminal 14 residues of RPN2 constitute the primary RPN13-docking epitope on the proteasome; ubiquitin, RPN2, and UCH37 bind RPN13 with independent energetics.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance, fluorescence polarization, mutational analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with quantitative binding measurements and mutagenesis\",\n      \"pmids\": [\"28442575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rpn13 activates Uch37 by disrupting Uch37 oligomeric autoinhibition: full-length Uch37 forms oligomers where catalytic domains block each other's ubiquitin-binding site; the C-terminal domain of Rpn13 (residues 270–407) sequesters Uch37 monomers into a 1:1 complex with 12-fold higher activity, as demonstrated by mutagenesis, NMR, SAXS, and FRET.\",\n      \"method\": \"Mutagenesis, NMR, SAXS, FRET, in vitro DUB activity assay (Ub-AMC)\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple structural and biochemical methods in one study\",\n      \"pmids\": [\"24752541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NMR structure of Rpn13 Pru domain with K48-diubiquitin shows bivalent interaction: proximal Ub binds similarly to monoubiquitin, while distal Ub contacts a largely electrostatic surface of Rpn13; a charge-reversal mutation weakening distal Ub binding causes accumulation of ubiquitinated proteins in cells, establishing the structural basis for Rpn13 K48-chain linkage selectivity.\",\n      \"method\": \"NMR structure determination, single-molecule FRET, mutagenesis, cell-based ubiquitin conjugate accumulation assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with smFRET confirmation and functional mutagenesis\",\n      \"pmids\": [\"30962947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NMR structure of hRpn13 Pru:hRpn2(940-953):K48-diubiquitin reveals that hRpn2-bound hRpn13 selects a dynamic, extended conformation of K48-diubiquitin distinct from the closed crystallographic conformation; hRpn13 exchanges between the two ubiquitins within 100 ms but prefers the proximal ubiquitin via interactions with the K48 linker region.\",\n      \"method\": \"NMR structure determination, NMR dynamics experiments\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with dynamics characterization\",\n      \"pmids\": [\"32160516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rpn13 is required for iNOS interaction with UCH37 and for iNOS degradation; IκB-α is also a substrate for the Rpn13/UCH37 complex, linking the Rpn13 pathway to NF-κB activation.\",\n      \"method\": \"siRNA knockdown, co-IP, degradation assays in cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — cell-based KD with specific substrate readouts, single lab\",\n      \"pmids\": [\"20634424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The double-capped 26S proteasome is structurally asymmetric: while both 19S particles contain Rpn10/S5a, only one of the two 19S caps contains Rpn13, as demonstrated by AQUA mass spectrometry and biochemical fractionation in both yeast and mammals.\",\n      \"method\": \"AQUA-MS quantification, biochemical fractionation, validated in yeast and mammals\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased quantitative MS with cross-species validation\",\n      \"pmids\": [\"24429290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rpn13 is the major proteasomal receptor for the E3 ubiquitin ligase parkin: the N-terminal Ubl domain of parkin binds directly to the Pru domain of Rpn13 with >10-fold higher affinity than ubiquitin; Rpn13 knockdown increases parkin levels, abrogates parkin recruitment to the proteasome, delays clearance of mitochondrial proteins during mitophagy, and enhances parkin autoubiquitination.\",\n      \"method\": \"NMR, mutational analysis, Co-IP, siRNA knockdown, affinity measurements, cell-based mitophagy assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — NMR mapping + reciprocal Co-IP + KD phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"25666615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rpn13 and Rpn10 function as redundant ubiquitin receptors in the mammalian liver: simultaneous liver-specific knockout of both causes severe liver injury and massive accumulation of ubiquitin conjugates, and mHR23B and ubiquilin/Plic-1/4 shuttle proteins fail to bind the proteasome only when both receptors are absent.\",\n      \"method\": \"Conditional double-knockout mice (liver-specific), co-IP, Western blot for ubiquitin conjugates, rescue experiments\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double KO with defined phenotype and rescue, validated in mouse\",\n      \"pmids\": [\"26222436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUMOylation of proteasomal scaffolding protein Psmd1/RPN2 at a lysine immediately adjacent to its Adrm1-binding domain, catalyzed by PIASy, regulates the association of Adrm1 with Psmd1; the SUMO deconjugating enzyme xSENP1 interacts with Psmd1 and its disruption delays mitotic exit.\",\n      \"method\": \"Xenopus egg extract system, SUMO site mapping, co-IP, cell-based mitotic exit assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — SUMOylation site mapped with functional consequence on Adrm1 binding, single lab\",\n      \"pmids\": [\"24910440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The C-terminal region of Rpn13 binds the TPR domain of SGTA (cochaperone for mislocalised membrane proteins); SGTA overexpression increases mislocalised membrane protein levels in a manner dependent on its interaction with Rpn13, suggesting SGTA can regulate substrate access to the proteasome via Rpn13.\",\n      \"method\": \"Co-IP, pulldown, SGTA/Rpn13 mutational analysis, cell-based substrate degradation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct binding and functional KD/OE assay, single lab\",\n      \"pmids\": [\"26169395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SGTA interacts with the proteasomal ubiquitin receptor Rpn13 through a carboxylate clamp mechanism involving the TPR domain of SGTA and a defined region of the Rpn13 C-terminal domain; structural and biophysical characterization confirmed this interface mediates Rpn13-SGTA association in cells.\",\n      \"method\": \"Structural and biophysical characterization (ITC, NMR, X-ray), mutagenesis, cell-based co-IP\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural characterization with mutagenesis and cellular validation\",\n      \"pmids\": [\"27827410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In mice, Rpn13 deletion produces tissue-specific effects on proteasomal function (increased activity in adrenal gland and lymphoid organs, decreased in testes and brain), infertility due to defective gametogenesis, and elevated serum growth hormone/FSH, while Uch37 deletion causes prenatal lethality with severe embryonic brain defects.\",\n      \"method\": \"Whole-body knockout mice, proteasome activity assays in tissues, hormone measurements, histology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined tissue-specific phenotypes, single lab\",\n      \"pmids\": [\"21048919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phosphorylation of RPN2 Tyr-950 by Jurkat cell kinase(s) enhances RPN13 binding affinity; a 1.76-Å crystal structure of the RPN2-RPN13 pTyr-950-ubiquitin complex reveals specific interactions with positively charged RPN13 residues that explain affinity increase without conformational change.\",\n      \"method\": \"X-ray crystallography, mutagenesis, quantitative binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and quantitative binding, single lab\",\n      \"pmids\": [\"31064842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A 38-amino acid peptide from the C-terminus of hRpn2/PSMD1 binds the hRpn13 Pru domain with 12 nM affinity and displaces endogenous Rpn13 from the proteasome in 293T cells; overexpression of this peptide leads to accumulation of ubiquitinated proteins.\",\n      \"method\": \"NMR epitope mapping, fluorescence polarization binding assay, co-IP, cell-based ubiquitin conjugate assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — NMR mapping plus quantitative affinity measurement and cell-based validation\",\n      \"pmids\": [\"26466095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Phospho-ΔNp63α binds to the RPN13 promoter (via a TP63-responsive element, in association with DDIT3/CHOP, NF-Y, NF-κB) to activate RPN13 gene transcription in response to cisplatin; this leads to NOS2/iNOS degradation, and RPN13 knockdown rescues NOS2 from cisplatin-dependent inactivation.\",\n      \"method\": \"ChIP, promoter-reporter assay, siRNA knockdown, protein degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP and functional knockdown, single lab\",\n      \"pmids\": [\"20959455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC8 physically interacts with the proteasome receptor ADRM1; inhibition of HDAC8 decreases MGMT protein levels in glioblastoma cells, and this regulation is disrupted by temozolomide specifically in TMZ-sensitive cells, suggesting that the HDAC8-ADRM1 interaction regulates MGMT levels independently of promoter methylation.\",\n      \"method\": \"Co-IP (HDAC8-ADRM1 interaction), HDAC8 inhibitor/shRNA, Western blot for MGMT\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with pharmacological/shRNA follow-up, mechanism not fully reconstituted\",\n      \"pmids\": [\"31798765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Adrm1 interacts with Atp6v0d2 (V-ATPase V0 domain d2 subunit) as identified by yeast two-hybrid and confirmed by co-immunoprecipitation in vivo; Adrm1 is required for osteoclast cell migration and maturation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown in osteoclast differentiation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid confirmed by single Co-IP, limited mechanistic follow-up\",\n      \"pmids\": [\"19818731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RPN13/ADRM1 Pru domain functions as a proteasomal receptor for MHC class I antigen processing: both Rpn10 and Rpn13 regulate processing of the NY-ESO-1 cancer/testis antigen and supply of HLA-A*0201-restricted peptides, with non-lysine ubiquitination sites governing this process.\",\n      \"method\": \"siRNA knockdown of Rpn13/Rpn10, antigen presentation assay, ubiquitination site mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — genetic KD with specific antigen-presentation readout, single lab\",\n      \"pmids\": [\"26903513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADRM1/Rpn13 acts as a resection inhibitor in DNA end processing; during DNA double-strand break repair, ADRM1 is removed from the CDW19S complex (a proteasome variant decorated with CRL4WDR70 ubiquitin ligase) by CRL4WDR70-catalyzed ubiquitination, permitting MRE11 and EXO1 nuclease-mediated resection; HBx stabilizes ADRM1, imposing a resection barrier and causing viral homologous recombination deficiency.\",\n      \"method\": \"Co-IP, chromatin fractionation, knockdown/knockout, in vitro and cell-based resection assays, xenograft models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and cell-based methods identifying novel non-proteasomal function, single lab\",\n      \"pmids\": [\"37815873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADRM1/Rpn13 upregulates UCH37 expression and activates its deubiquitination activity; activated UCH37 then deubiquitinates ALK5 to stabilize it, maintaining extracellular matrix homeostasis in articular cartilage; global ADRM1 KO accelerates cartilage degeneration in a DMM mouse model.\",\n      \"method\": \"Knockout mice, overexpression in vivo, in vitro deubiquitination assay, co-IP (ADRM1-UCH37), Western blot for ALK5 ubiquitination\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo KO phenotype plus mechanistic biochemistry, single lab\",\n      \"pmids\": [\"37406898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel splice variant of ADRM1 lacking exon 9 (ADRM1-ΔEx9) interacts with deubiquitinase BAP1 (instead of UCH37) via its shortened C-terminus, altering proteasome specificity; the exon 8-10 fusion creates a de novo binding site for tumor suppressor FBXW7, leading to its selective proteasome-mediated degradation and promoting hepatocellular carcinoma.\",\n      \"method\": \"SMRT sequencing, human organoids, hydrodynamic in vivo transfection mouse model, Proteome Profiler Ubiquitin Array, co-IP (ADRM1-ΔEx9-BAP1, ADRM1-ΔEx9-FBXW7), patient-derived xenografts\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel splice variant with multiple experimental systems, single lab\",\n      \"pmids\": [\"39788431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Protea-Tac, a heterobifunctional degrader using ADRM1/Rpn13 as the proteasome-targeting moiety fused to a target-specific intracellular antibody, integrates into 26S proteasomes without altering their integrity and degrades substrates (c-Fos, BRD4, tau, TDP43, GFP-ODC) in a ubiquitin-independent manner via direct proteasomal targeting.\",\n      \"method\": \"Reconstitution of chimeric degrader in cells, proteasome structural/functional integrity assays, in vivo xenograft mouse model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — modular system with multiple substrates and in vivo validation, but preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ADRM1/hRpn13 is a stoichiometric 19S proteasome subunit that docks onto the C-terminus of RPN2/PSMD1 (a phosphorylatable interaction modulated by SUMOylation of RPN2) via its N-terminal Pru domain, which simultaneously serves as the ubiquitin receptor preferentially recognizing K48-linked polyubiquitin chains through bivalent contacts with both proximal and distal ubiquitin moieties; its C-terminal DEUBAD domain recruits and allosterically activates the deubiquitinating enzyme UCH37/UCHL5 by disrupting UCH37 autoinhibitory oligomerization, coupling ubiquitin chain recognition with distal-end chain disassembly at the proteasome; one of the two 19S caps in double-capped 26S proteasomes contains Rpn13, creating structural asymmetry; Rpn13 is also autoubiquitinated by proteasome-associated Ube3c/Hul5 under proteotoxic stress, reducing ubiquitin-conjugate binding as a feedback mechanism; and in addition to its canonical proteasomal role, ADRM1 participates in DNA double-strand break resection control, MHC class I antigen processing, parkin recruitment to the proteasome, and selective substrate degradation including iNOS, IκB-α, and ALK5 via the Rpn13/UCH37 axis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADRM1 (hRpn13) is a stoichiometric 19S proteasome subunit that functions as a ubiquitin receptor and scaffold for deubiquitination at the proteasome, coupling substrate recognition to ubiquitin chain processing. Its N-terminal Pru domain docks onto the C-terminus of RPN2/PSMD1 and simultaneously recognizes K48-linked polyubiquitin chains through bivalent contacts with proximal and distal ubiquitin moieties, while its C-terminal DEUBAD domain recruits and allosterically activates UCH37/UCHL5 by disrupting UCH37 autoinhibitory oligomerization [PMID:18497817, PMID:16906146, PMID:25702870, PMID:24752541, PMID:30962947]. ADRM1 functions redundantly with RPN10 as proteasomal ubiquitin receptors; simultaneous loss of both in mouse liver causes massive ubiquitin-conjugate accumulation and organ failure, and its autoubiquitination by proteasome-associated Ube3c under proteotoxic stress serves as a feedback mechanism to reduce substrate engagement [PMID:26222436, PMID:24811749]. Beyond canonical proteasomal proteolysis, ADRM1 participates in MHC class I antigen processing, parkin recruitment during mitophagy, and DNA double-strand break resection control, where its CRL4-WDR70-mediated removal from a proteasome variant permits MRE11/EXO1 nuclease activity [PMID:26903513, PMID:25666615, PMID:37815873].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing ADRM1 as a bona fide stoichiometric proteasome subunit answered whether it was a transient interactor or an integral 19S component, and revealed it as the anchor for deubiquitinase UCH37.\",\n      \"evidence\": \"Co-IP, native PAGE, gel filtration, and in vitro DUB assays in reconstituted subcomplexes and human cells\",\n      \"pmids\": [\"16815440\", \"16906146\", \"17139257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How ADRM1 is incorporated during proteasome assembly was not addressed\",\n        \"Whether ADRM1 directly binds ubiquitin was unknown at this stage\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying ADRM1 as a direct ubiquitin receptor via its Pru domain resolved how ubiquitinated substrates are recognized at the proteasome beyond RPN10, and genetic epistasis in yeast established functional redundancy between the two receptors.\",\n      \"evidence\": \"ITC, NMR, and yeast double-mutant synthetic lethality\",\n      \"pmids\": [\"18497817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for polyubiquitin chain linkage selectivity was not yet determined\",\n        \"How Pru domain simultaneously accommodates RPN2 docking and ubiquitin binding was unclear\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mouse knockout studies revealed that Rpn13 loss produces tissue-specific rather than globally lethal phenotypes (unlike UCH37 deletion), establishing that Rpn13 is dispensable for viability but critical for gametogenesis and specific tissues.\",\n      \"evidence\": \"Whole-body Rpn13 and Uch37 knockout mice with tissue proteasome activity profiling\",\n      \"pmids\": [\"21048919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Why certain tissues (testes, brain) are selectively vulnerable to Rpn13 loss is unexplained\",\n        \"Compensatory mechanisms by RPN10 or shuttle receptors in surviving tissues were not dissected\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking the Rpn13/UCH37 axis to specific substrate degradation (iNOS, IκB-α) and to transcriptional regulation of RPN13 by ΔNp63α established that the receptor can direct selective proteolysis with pathway-level consequences for NF-κB signaling.\",\n      \"evidence\": \"siRNA knockdown, co-IP, ChIP on RPN13 promoter, substrate degradation assays\",\n      \"pmids\": [\"20634424\", \"20959455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Rpn13/UCH37 selectivity for iNOS/IκB-α reflects direct substrate recognition or indirect effects was not resolved\",\n        \"Generality of transcriptional regulation of RPN13 expression beyond the cisplatin/ΔNp63α axis is unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that only one of two 19S caps in double-capped 26S proteasomes contains Rpn13 established intrinsic structural asymmetry, raising the possibility that the two caps have distinct substrate-processing capabilities.\",\n      \"evidence\": \"AQUA mass spectrometry and biochemical fractionation in yeast and mammals\",\n      \"pmids\": [\"24429290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequences of this asymmetry for substrate selection and processing are unknown\",\n        \"What determines which cap receives Rpn13 is not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of Rpn13 autoubiquitination by proteasome-associated Ube3c under proteotoxic stress revealed a feedback mechanism that reduces the proteasome's ability to capture new ubiquitinated substrates when proteolysis is impaired.\",\n      \"evidence\": \"In vitro ubiquitination with purified proteasomes, mass spectrometry, proteasome inhibitor treatments in cells\",\n      \"pmids\": [\"24811749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How autoubiquitinated Rpn13 is subsequently resolved (deubiquitinated or degraded) is unclear\",\n        \"Whether this feedback operates physiologically outside of inhibitor treatment is not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Structural and biophysical dissection of how Rpn13 disrupts UCH37 autoinhibitory oligomers into active 1:1 complexes resolved the allosteric activation mechanism, explaining how deubiquitination is spatially coupled to substrate recognition.\",\n      \"evidence\": \"Mutagenesis, NMR, SAXS, FRET, and in vitro DUB assays\",\n      \"pmids\": [\"24752541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the Rpn13–UCH37 complex coordinates with other proteasomal DUBs (Rpn11/USP14) during substrate processing was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures of the DEUBAD–UCH37 complex revealed the molecular basis for Rpn13-mediated activation versus INO80G-mediated inhibition of the same enzyme, establishing a paradigm of DEUBAD-domain molecular mimicry.\",\n      \"evidence\": \"Crystal structures with mutagenesis and activity assays\",\n      \"pmids\": [\"25702870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the switch between activating (Rpn13) and inhibiting (INO80G) DEUBAD contexts is regulated in vivo is not known\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"In vivo double-knockout of Rpn13 and Rpn10 in mouse liver proved their functional redundancy as the essential proteasomal ubiquitin receptors and showed that UBL-UBA shuttle proteins require at least one intrinsic receptor for proteasome docking.\",\n      \"evidence\": \"Liver-specific conditional double-knockout mice with co-IP and rescue experiments\",\n      \"pmids\": [\"26222436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other tissues exhibit the same strict redundancy or have additional compensatory mechanisms is untested\",\n        \"Individual contribution of each receptor to specific substrate classes in vivo is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of Rpn13 as the major proteasomal receptor for the E3 ligase parkin, with its Ubl domain binding the Pru domain at higher affinity than ubiquitin, connected Rpn13 to mitophagy and Parkinson's disease-relevant biology.\",\n      \"evidence\": \"NMR, quantitative binding assays, reciprocal co-IP, siRNA, and cell-based mitophagy assay\",\n      \"pmids\": [\"25666615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Rpn13-dependent parkin recruitment is relevant in dopaminergic neurons in vivo is untested\",\n        \"Competition between parkin-Ubl and ubiquitin for the Pru domain under physiological conditions is not quantified\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Crystal structures of the Pru–RPN2 and Pru–ubiquitin interfaces resolved the overlapping binding surfaces, explaining how Rpn13 integrates proteasome docking with ubiquitin recognition and clarifying how RA190 targets this interface.\",\n      \"evidence\": \"X-ray crystallography, SPR, NMR, mutagenesis in HCT116 ADRM1-deleted cells\",\n      \"pmids\": [\"28598414\", \"28442575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How Rpn13 simultaneously engages RPN2 and ubiquitin on a shared surface in the context of the intact proteasome is structurally unresolved at full 26S resolution\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"NMR structure of the Pru–K48-diubiquitin complex revealed bivalent chain recognition through distinct proximal and distal ubiquitin contacts, providing the structural basis for K48-linkage selectivity; RPN2 Tyr-950 phosphorylation was shown to enhance Rpn13 binding, adding a layer of post-translational regulation.\",\n      \"evidence\": \"NMR structures, smFRET, charge-reversal mutagenesis with cellular validation; crystal structure of pTyr-950–RPN2–Rpn13–Ub\",\n      \"pmids\": [\"30962947\", \"31064842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The kinase(s) responsible for RPN2 Tyr-950 phosphorylation in vivo and its regulation are not identified\",\n        \"How bivalent K48-diUb binding transitions to chain handoff to UCH37 or Rpn11 is mechanistically unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of ADRM1 as a resection inhibitor in DNA double-strand break repair, removed by CRL4-WDR70 ubiquitination to permit MRE11/EXO1 activity, established a non-proteasomal function for ADRM1 in genome integrity.\",\n      \"evidence\": \"Co-IP, chromatin fractionation, knockout, in vitro and cell-based resection assays, xenograft models\",\n      \"pmids\": [\"37815873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The mechanism by which ADRM1 physically blocks resection is not structurally defined\",\n        \"Whether this function is independent of UCH37 and proteasome catalytic activity is not fully dissected\",\n        \"Confirmation by independent laboratories is needed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a cancer-associated splice variant (ADRM1-ΔEx9) that switches partner binding from UCH37 to BAP1 and creates a neo-binding site for FBXW7, directing its proteasomal degradation, revealed how alternative splicing can reprogram Rpn13 substrate specificity to promote hepatocellular carcinoma.\",\n      \"evidence\": \"SMRT sequencing, human organoids, hydrodynamic transfection mouse models, co-IP, patient-derived xenografts\",\n      \"pmids\": [\"39788431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Prevalence and regulation of the ΔEx9 splice variant across cancer types is not characterized\",\n        \"Structural basis for BAP1 binding by the shortened C-terminus is not determined\",\n        \"Independent replication is needed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how Rpn13 coordinates with other proteasomal deubiquitinases (Rpn11, USP14) during processive substrate degradation, what determines asymmetric Rpn13 occupancy on double-capped proteasomes, and the in vivo physiological relevance of the Rpn13 autoubiquitination feedback loop.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No full-resolution cryo-EM structure of Rpn13-engaged substrate processing intermediate exists\",\n        \"In vivo dynamics of Rpn13 autoubiquitination and its reversal are unmeasured\",\n        \"Tissue-specific proteasome composition incorporating Rpn13 splice variants has not been systematically profiled\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 14, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"complexes\": [\n      \"26S proteasome 19S regulatory particle\"\n    ],\n    \"partners\": [\n      \"UCHL5\",\n      \"PSMD1\",\n      \"PSMD4\",\n      \"PRKN\",\n      \"SGTA\",\n      \"UBE3C\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}