{"gene":"UBE2J2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1997,"finding":"Ubc6p (yeast ortholog of UBE2J2) is a membrane-bound ER ubiquitin-conjugating enzyme that works together with Cue1p-assembled Ubc7p to ubiquitinate ERAD substrates; ubiquitination by this pair is a prerequisite for retrograde transport of lumenal substrates out of the ER.","method":"Genetic (deletion mutants), biochemical fractionation, ERAD substrate degradation assays in yeast","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods, replicated across multiple subsequent studies","pmids":["9388185"],"is_preprint":false},{"year":2000,"finding":"Ubc6p/Ubc7p ubiquitin-conjugating enzyme pair recognizes cytosolic degradation signals containing a patch of bulky hydrophobic residues and positively charged residues; ubiquitination of these substrates occurs on the cytosolic face of the ER without prior transfer to the ER lumen, independently of Hrd1p/Der3p and Sec61p retrograde transport.","method":"Genetic analysis with deletion mutants (hrd1/der3Δ, sec61-2), fusion protein degradation assays, mutational analysis of degron sequences in yeast","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic backgrounds tested, mutagenesis of signal sequences, clear epistasis results","pmids":["10982838"],"is_preprint":false},{"year":2001,"finding":"The tail-anchored ER membrane protein Ubc6p undergoes self-ubiquitination-dependent degradation that requires its own catalytic site cysteine and Cue1p-assembled Ubc7p, but is independent of Ubc1p, Hrd1p/Der3p, Hrd3p, Der1p, and the Sec61p translocon; a membrane-bound degradation intermediate accumulates in proteasome mutants.","method":"Genetic deletion mutants, sec61 mutants, pulse-chase degradation assays, proteasome mutant analysis in yeast","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive genetic epistasis across multiple deletion/mutant backgrounds with biochemical readout","pmids":["11406589"],"is_preprint":false},{"year":2001,"finding":"Murine UBE2J2 (MmUbc6) is an integral membrane protein anchored via its hydrophobic C-terminal tail to the endoplasmic reticulum; overexpression of catalytically inactive MmUbc7 (not MmUbc6 dominant-negative) significantly delayed ERAD of T cell receptor alpha and CD3-delta subunits, implicating these ER-localized E2s in mammalian ERAD.","method":"Immunofluorescence colocalization, dominant-negative overexpression, pulse-chase degradation assays in mammalian cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments plus functional dominant-negative assays, single lab","pmids":["11278356"],"is_preprint":false},{"year":2002,"finding":"Two families of mammalian Ubc6p-related proteins (including UBE2J2/NCUBE2) are localized to the ER membrane with the same cytoplasmic-face topology as yeast Ubc6p; expression of wild-type and dominant-negative alleles specifically affects ERAD of TCR-alpha and mutant CFTR, and elevated Ubc6p levels in yeast also affect ERAD, indicating highly conserved function.","method":"Subcellular fractionation, topology assays, dominant-negative overexpression, ERAD substrate degradation assays in mammalian cells and yeast","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal methods (localization, topology, functional dominant-negative in both mammalian cells and yeast), two substrates tested","pmids":["12082160"],"is_preprint":false},{"year":2006,"finding":"Human UBE2J2 (hsUbc6) possesses tail-anchored protein motifs, is localized to the ER, is a functional ubiquitin-conjugating enzyme as shown by in vitro thiol-ester assay, and its expression is induced by the unfolded protein response.","method":"In vitro ubiquitin thiol-ester assay, subcellular localization, UPR induction experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay confirms E2 activity, localization confirmed, single lab","pmids":["16720581"],"is_preprint":false},{"year":2009,"finding":"UBE2J2 is the primary cellular E2 recruited by the viral E3 ligase mK3 for ERAD; the UBE2J2-mK3 pair preferentially ubiquitinates hydroxylated amino acids (serine/threonine) on ERAD substrates via ester bonds even when lysine residues are present, establishing that noncanonical ubiquitination of hydroxylated residues is physiologically relevant.","method":"E2 identification by co-immunoprecipitation/pulldown, in vitro ubiquitination assay with lysine-less substrate mutants, mass spectrometry of ubiquitin linkages","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis and biochemical demonstration of ester bond ubiquitination, multiple substrate variants tested","pmids":["19951915"],"is_preprint":false},{"year":2014,"finding":"UBE2J2 is essential for US11-mediated ERAD of HLA class I molecules; TMEM129 (an E3 ligase) together with UBE2J2 (as its cognate E2) is responsible for ubiquitination, dislocation, and degradation of US11-associated MHC-I via a Derlin-1-dependent ERAD complex.","method":"Genome-wide shRNA screen, CRISPR forward genetic screen in near-haploid cells, Co-IP, functional degradation assays","journal":"Nature communications / PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genetic screens (shRNA and insertional mutagenesis) converged on UBE2J2, functional validation by multiple labs","pmids":["24807418","25030448"],"is_preprint":false},{"year":2014,"finding":"UBE2J2 is itself an unstable protein subject to proteasomal degradation; proteasomal inhibitors increase its steady-state levels. This effect requires both catalytic activity and ER localization (disruption of either stabilizes the enzyme), suggesting auto-ubiquitination-linked turnover.","method":"Proteasome inhibitor treatment, catalytic mutants, truncation mutants, immunoblot in transfected mammalian cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological and genetic approaches, single lab, no direct ubiquitination demonstrated","pmids":["25083800"],"is_preprint":false},{"year":2017,"finding":"UBE2J2, in contrast to UBE2J1, is not essential for recovery from transient ER stress; Ube2j1 (not Ube2j2) is the E2 whose phosphorylation by MAPK signaling mediates ER stress recovery, and c-IAP1 preferentially interacts with phosphorylated Ube2j1.","method":"Ectopic expression of wild-type and phospho-mutant constructs, cell viability assays, Co-IP in mammalian cells","journal":"Journal of cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional rescue assays and Co-IP, negative result for UBE2J2 role in ER stress recovery is a mechanistically informative distinction, single lab","pmids":["28321712"],"is_preprint":false},{"year":2017,"finding":"UBE2J2 counteracts US2-induced ERAD by downregulating TRC8 (RNF139) E3 ligase expression; in contrast, UBE2G2 is the crucial E2 for US2-mediated HLA-I degradation, demonstrating distinct roles for different E2s in HCMV immune evasion.","method":"Lentiviral CRISPR/Cas9 library screening targeting all human E2 enzymes, functional degradation assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale CRISPR screen with functional follow-up, single lab","pmids":["28743740"],"is_preprint":false},{"year":2018,"finding":"UBE2J2 functions as the E2 ubiquitin-conjugating enzyme for the E3 ligase CGRRF1 to ubiquitinate the Wnt cargo receptor Evi/Wls for ERAD in the absence of Wnt ligands, thereby regulating Wnt protein secretion.","method":"RNAi knockdown, co-immunoprecipitation, ERAD substrate stability assays in mammalian cells","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with functional ERAD readout plus E2-E3 interaction demonstrated, single lab","pmids":["29378775"],"is_preprint":false},{"year":2018,"finding":"UBE2J2 is the primary E2 ubiquitin-conjugating enzyme essential for MARCH6-dependent cholesterol-stimulated degradation of squalene monooxygenase (SQLE), but not for sterol-dependent degradation of HMGCR (which requires UBE2G2), revealing substrate-specific E2 usage in ERAD.","method":"CRISPR/Cas9-based screen for ERAD E2 enzymes, catalytic mutant rescue, cholesterol-stimulated degradation assays in multiple human cell types","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen, catalytic mutant dependency, multiple human cell types including hepatic cells, enzymatic activity shown to be required","pmids":["30658189"],"is_preprint":false},{"year":2019,"finding":"US11 recruits Derlin-1, TMEM129, and UBE2J2 to engage FcRn, initiating dislocation of FcRn from the ER to the cytosol and its degradation, thereby inhibiting IgG-FcRn binding and IgG transport.","method":"Co-immunoprecipitation, ERAD substrate degradation assays, functional IgG transcytosis assays in mammalian cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP complex formation and functional degradation demonstrated, single lab","pmids":["31289263"],"is_preprint":false},{"year":2021,"finding":"UBE2J2, together with UBE2K and UBE2N, mediates K11-, K48-, and K63-linked ubiquitylation of EVI/WLS, independently of E3 ligases HRD1 and GP78; ERLIN2 links EVI/WLS to the ubiquitylation machinery.","method":"RNAi screen, Co-IP, ubiquitin linkage analysis, E3 ligase independence assays in mammalian cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi screen plus Co-IP, ubiquitin linkage typing, single lab","pmids":["34406391"],"is_preprint":false},{"year":2023,"finding":"Ube2j2 functions cooperatively with Ube2k as E2 ubiquitin-conjugating enzymes with the E3 ligase March5 at the mitochondria; depletion of Ube2j2 sensitizes AML cells to Venetoclax specifically in the presence of March5, and March5 controls Noxa levels to regulate Bax-Mcl1 interactions in the apoptosis pathway.","method":"Genome-wide CRISPR/Cas9 screens, genetic knockouts, CRISPR epistasis screens in mouse AML cells","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screens with epistasis and functional apoptosis readouts, single lab","pmids":["36973350"],"is_preprint":false},{"year":2024,"finding":"X-ray crystallography and MD simulations of Ubc6/UBE2J2 revealed a two-layered mechanism for serine ubiquitination: (1) rearrangement of the active site enhances E2-Ub thioester reactivity toward weak nucleophiles; (2) a conserved histidine in Ubc6/UBE2J2 activates substrate serine via general base catalysis. RING-type E3 ligases further increase serine selectivity via an allosteric mechanism requiring specific positioning of the ubiquitin tail at the E2 active site.","method":"X-ray crystallography, molecular dynamics simulations, in vitro reconstitution ubiquitination assays, active-site mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus MD simulations plus reconstitution and mutagenesis in a single rigorous study","pmids":["39533056"],"is_preprint":false},{"year":2025,"finding":"UBE2J2 acts as a membrane lipid sensor in ERAD: in loosely packed membranes, its transmembrane domain associates with membrane lipids in a way that impedes ubiquitin loading (rendering it inactive), while tighter lipid packing promotes an active conformation and interaction with E1. This activity directs ubiquitin transfer by multiple E3 ligases (RNF145, MARCHF6, RNF139) targeting themselves and the substrate squalene monooxygenase.","method":"In vitro reconstitution with purified ERAD factors, lipid-composition modulation of proteoliposomes, ubiquitination assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — fully reconstituted system with purified components and defined lipid compositions, multiple E3 ligase partnerships demonstrated","pmids":["41068091"],"is_preprint":false},{"year":2025,"finding":"UBE2J2 is essential for male meiosis in mice; Ube2j2 knockout male mice are azoospermic with spermatocytes arrested at mid-pachytene stage, exhibiting unstable homologous recombination intermediate complexes that fail to form crossovers, and loss of a broad set of meiosis- and chromosome segregation-associated proteins.","method":"Knockout mouse model, histology, immunofluorescence of HR markers (e.g., MLH1, RPA), proteomics of spermatocytes","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined cellular phenotype and proteomic characterization, single lab, mechanism of action (beyond ERAD context) not fully resolved","pmids":["40686610"],"is_preprint":false}],"current_model":"UBE2J2 (human ortholog of yeast Ubc6p) is a tail-anchored, ER membrane-localized E2 ubiquitin-conjugating enzyme whose active site uniquely enables both canonical lysine ubiquitination and noncanonical serine/threonine ester-bond ubiquitination through a histidine-mediated general base catalysis mechanism; it functions as the primary E2 for multiple ERAD E3 ligases (including TMEM129, MARCH6/MARCHF6, CGRRF1, RNF145, and RNF139) to ubiquitinate diverse substrates (MHC-I, squalene monooxygenase, EVI/WLS, FcRn), and additionally acts as a sensor for membrane lipid saturation—with its transmembrane domain toggling between active and inactive states depending on lipid packing—thereby coupling ER membrane homeostasis to ERAD activity."},"narrative":{"mechanistic_narrative":"UBE2J2 is a tail-anchored, ER membrane-localized E2 ubiquitin-conjugating enzyme that serves as a central conjugating component of endoplasmic-reticulum-associated degradation (ERAD), conserved from its yeast ortholog Ubc6p, which ubiquitinates ERAD substrates on the cytosolic face of the ER as a prerequisite for their retrotranslocation and proteasomal degradation [PMID:9388185, PMID:12082160]. It is anchored to the ER via a hydrophobic C-terminal tail with cytosolic-facing catalytic topology, is a functional E2 by in vitro thiol-ester assay, and is induced by the unfolded protein response [PMID:11278356, PMID:16720581]. A defining feature of UBE2J2 is its capacity for noncanonical ubiquitination: it ubiquitinates serine/threonine residues through ester bonds even when lysines are available, a chemistry enabled by an active-site rearrangement that boosts E2-Ub thioester reactivity and a conserved histidine acting as a general base to activate the substrate hydroxyl, with RING E3 ligases sharpening serine selectivity allosterically [PMID:19951915, PMID:39533056]. UBE2J2 functions as the cognate E2 for a broad set of ER-membrane E3 ligases—TMEM129, MARCH6/MARCHF6, CGRRF1, RNF145, and RNF139—to ubiquitinate substrates including MHC class I, FcRn, the Wnt cargo receptor EVI/WLS, and squalene monooxygenase, with substrate- and ligase-specific E2 usage that distinguishes it from UBE2G2 [PMID:24807418, PMID:25030448, PMID:29378775, PMID:30658189, PMID:31289263, PMID:41068091]. It is exploited by viral E3 ligases (mK3, US11) to drive immune-evasion degradation of MHC-I and FcRn [PMID:19951915, PMID:24807418, PMID:25030448, PMID:31289263]. Beyond catalysis, UBE2J2 acts as a membrane lipid-packing sensor whose transmembrane domain toggles between ubiquitin-loading-competent and inactive states with lipid order, coupling ER membrane homeostasis to ERAD output [PMID:41068091]. UBE2J2 is itself an unstable, catalysis- and ER-localization-dependent substrate of proteasomal turnover [PMID:25083800], and is required for male meiotic progression in mice, where its loss arrests spermatocytes at mid-pachytene with defective crossover formation [PMID:40686610].","teleology":[{"year":1997,"claim":"Established that an ER membrane-bound E2 (yeast Ubc6p, ortholog of UBE2J2) is a required upstream actor in ERAD, linking ubiquitination to retrograde extraction of misfolded substrates.","evidence":"Genetic deletion mutants and ERAD substrate degradation assays in yeast","pmids":["9388185"],"confidence":"High","gaps":["Did not define the mammalian ortholog's role","Site of ubiquitin attachment and substrate range unresolved"]},{"year":2000,"claim":"Resolved where ubiquitination occurs by showing the Ubc6p/Ubc7p pair acts on cytosolic degrons on the ER's cytosolic face, independent of luminal transfer and Sec61/Hrd1.","evidence":"Genetic epistasis and degron mutagenesis in yeast","pmids":["10982838"],"confidence":"High","gaps":["Substrate-recognition determinants in mammals untested","E3 ligase partners for these degrons not fully mapped"]},{"year":2001,"claim":"Defined UBE2J2 as a tail-anchored ER integral membrane protein in mammals and implicated ER-localized E2s in mammalian ERAD of TCR and CD3 subunits.","evidence":"Immunofluorescence, dominant-negative overexpression, pulse-chase in mammalian cells; yeast self-ubiquitination/turnover assays","pmids":["11278356","11406589"],"confidence":"High","gaps":["Direct catalytic requirement of UBE2J2 (vs UBE2J1/Ubc7) for specific substrates not isolated","Cognate E3 ligases in mammals unidentified"]},{"year":2002,"claim":"Confirmed conserved cytoplasmic-face topology and ERAD function of mammalian Ubc6p-related E2s across species, generalizing the role to multiple substrates (TCR-alpha, mutant CFTR).","evidence":"Fractionation, topology assays, dominant-negative ERAD assays in mammalian cells and yeast","pmids":["12082160"],"confidence":"High","gaps":["Endogenous loss-of-function effects not tested","Specific E2-E3 pairings undefined"]},{"year":2006,"claim":"Confirmed human UBE2J2 is a bona fide functional E2 with tail-anchor motifs and UPR-inducible expression, embedding it in the ER stress response.","evidence":"In vitro thiol-ester assay, localization, UPR induction in mammalian cells","pmids":["16720581"],"confidence":"Medium","gaps":["No substrate or E3 partner defined in this study","Single-lab in vitro activity"]},{"year":2009,"claim":"Discovered that UBE2J2 catalyzes noncanonical ester-bond ubiquitination of serine/threonine even in the presence of lysines, redefining the chemistry of ubiquitin transfer it can perform.","evidence":"E2 pulldown, in vitro ubiquitination with lysine-less substrates, mass spectrometry of linkages (viral E3 mK3)","pmids":["19951915"],"confidence":"High","gaps":["Structural basis of ester-bond catalysis not yet resolved","Generality across cellular E3 ligases untested"]},{"year":2014,"claim":"Identified UBE2J2 as the cognate E2 for the E3 TMEM129 in US11-driven MHC-I dislocation, establishing a specific E2-E3 axis in viral immune evasion.","evidence":"Genome-wide shRNA and CRISPR haploid screens, Co-IP, degradation assays","pmids":["24807418","25030448"],"confidence":"High","gaps":["Whether the same axis operates on endogenous MHC-I turnover unclear","Role of ester vs lysine linkage on this substrate not dissected"]},{"year":2014,"claim":"Showed UBE2J2 is itself an unstable protein turned over by the proteasome in a manner dependent on its catalytic activity and ER localization, implying auto-regulatory turnover.","evidence":"Proteasome inhibitors, catalytic and truncation mutants, immunoblot","pmids":["25083800"],"confidence":"Medium","gaps":["Direct auto-ubiquitination not demonstrated","Responsible E3, if any, not identified"]},{"year":2017,"claim":"Distinguished UBE2J2 from its paralog UBE2J1 by showing UBE2J2 is dispensable for ER stress recovery and is not the MAPK-phosphorylated/c-IAP1-interacting E2, sharpening functional non-redundancy.","evidence":"Phospho-mutant constructs, viability assays, Co-IP in mammalian cells","pmids":["28321712"],"confidence":"Medium","gaps":["Whether UBE2J2 is regulated by any post-translational signal unknown","Negative result; single lab"]},{"year":2017,"claim":"Demonstrated E2 selectivity in viral ERAD, with UBE2J2 modulating TRC8/RNF139 levels while UBE2G2 drives US2-mediated HLA-I degradation, reinforcing E2-specific routing.","evidence":"Genome-scale CRISPR screen of all E2s with functional follow-up","pmids":["28743740"],"confidence":"Medium","gaps":["Mechanism by which UBE2J2 downregulates TRC8 not defined","Single lab"]},{"year":2018,"claim":"Expanded the substrate/E3 repertoire by establishing UBE2J2 as the E2 for CGRRF1-mediated EVI/WLS degradation (Wnt secretion control) and for MARCH6-dependent SQLE degradation (cholesterol-regulated sterol metabolism), with substrate-specific E2 usage versus UBE2G2.","evidence":"RNAi/CRISPR screens, Co-IP, catalytic-mutant rescue, ERAD stability assays in multiple human cell types","pmids":["29378775","30658189"],"confidence":"High","gaps":["Whether SQLE/EVI ubiquitination uses ester linkages unresolved","How E3 selection partitions substrates not mechanistically explained"]},{"year":2019,"claim":"Showed UBE2J2 within a Derlin-1/TMEM129 complex drives FcRn dislocation and degradation, providing a functional consequence (blockade of IgG transport) for its ERAD activity.","evidence":"Co-IP, degradation and IgG transcytosis assays in mammalian cells (US11 context)","pmids":["31289263"],"confidence":"Medium","gaps":["Endogenous (non-viral) FcRn regulation not addressed","Single lab"]},{"year":2021,"claim":"Revealed UBE2J2 can build K11/K48/K63 linkages on EVI/WLS cooperatively with UBE2K and UBE2N independently of HRD1/GP78, with ERLIN2 bridging substrate to machinery, broadening its linkage and partner range.","evidence":"RNAi screen, Co-IP, ubiquitin linkage typing, E3-independence assays","pmids":["34406391"],"confidence":"Medium","gaps":["Reconciliation with CGRRF1-dependent EVI degradation unclear","Direct E3 catalyzing these linkages not defined"]},{"year":2023,"claim":"Extended UBE2J2 function beyond the ER by showing it acts with UBE2K and the mitochondrial E3 MARCH5 to regulate Noxa/Bax-Mcl1 apoptotic signaling, modulating Venetoclax sensitivity in AML.","evidence":"Genome-wide CRISPR and epistasis screens, knockouts, apoptosis readouts in mouse AML cells","pmids":["36973350"],"confidence":"Medium","gaps":["Mitochondrial vs ER pool of UBE2J2 not distinguished","Direct mitochondrial substrate of UBE2J2 not identified"]},{"year":2024,"claim":"Provided the structural and mechanistic basis for serine ubiquitination: active-site rearrangement enhances thioester reactivity and a conserved histidine acts as a general base, with RING E3s adding allosteric serine selectivity.","evidence":"X-ray crystallography, MD simulations, in vitro reconstitution and active-site mutagenesis","pmids":["39533056"],"confidence":"High","gaps":["In-cell contribution of ester vs lysine linkages per substrate not quantified","Which physiological substrates are serine-ubiquitinated remains to be mapped"]},{"year":2025,"claim":"Demonstrated UBE2J2 is a membrane lipid-packing sensor whose transmembrane domain toggles ubiquitin-loading competence with lipid order, coupling ER membrane homeostasis to ERAD by multiple E3 ligases (RNF145, MARCHF6, RNF139).","evidence":"Reconstitution with purified ERAD factors and defined-lipid proteoliposomes, ubiquitination assays","pmids":["41068091"],"confidence":"High","gaps":["In-cell evidence that physiological lipid changes toggle activity not shown","How lipid sensing integrates with E3 selection unresolved"]},{"year":2025,"claim":"Established a physiological requirement for UBE2J2 in male meiosis, with knockout mice azoospermic due to mid-pachytene arrest, unstable recombination intermediates, and failed crossover formation.","evidence":"Knockout mouse model, histology, HR-marker immunofluorescence, spermatocyte proteomics","pmids":["40686610"],"confidence":"Medium","gaps":["Mechanistic link between UBE2J2 ubiquitination activity and recombination not defined","Whether ERAD substrates mediate the meiotic phenotype unknown"]},{"year":null,"claim":"It remains unknown which endogenous substrates are serine/ester-ubiquitinated in cells, how lipid sensing and E3 selection are integrated in vivo, and what molecular pathway connects UBE2J2 catalysis to meiotic recombination.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in-cell quantification of ester vs lysine linkage per substrate","Mechanism coupling ERAD/ubiquitination to meiotic crossover formation undefined","Physiological lipid triggers of the sensor not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,16,12,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5,6,16]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3,4,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,6,7,12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,10,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[18]}],"complexes":["Derlin-1/TMEM129/UBE2J2 ERAD dislocation complex"],"partners":["TMEM129","MARCHF6","CGRRF1","RNF145","RNF139","MARCH5","UBE2K","ERLIN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N2K1","full_name":"Ubiquitin-conjugating enzyme E2 J2","aliases":["E2 ubiquitin-conjugating enzyme J2","Non-canonical ubiquitin-conjugating enzyme 2","NCUBE-2"],"length_aa":259,"mass_kda":28.9,"function":"Catalyzes the covalent attachment of ubiquitin to other proteins. Seems to function in the selective degradation of misfolded membrane proteins from the endoplasmic reticulum (ERAD) (By similarity). In cooperation with the GATOR2 complex, catalyzes 'Lys-6'-linked ubiquitination of NPRL2 (PubMed:36528027)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8N2K1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBE2J2","classification":"Not Classified","n_dependent_lines":223,"n_total_lines":1208,"dependency_fraction":0.18460264900662252},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBE2J2","total_profiled":1310},"omim":[{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"619756","title":"UBIQUITIN-CONJUGATING ENZYME E2 J2; UBE2J2","url":"https://www.omim.org/entry/619756"},{"mim_id":"616175","title":"UBIQUITIN-CONJUGATING ENZYME E2 J1; UBE2J1","url":"https://www.omim.org/entry/616175"},{"mim_id":"615975","title":"TRANSMEMBRANE PROTEIN 129; TMEM129","url":"https://www.omim.org/entry/615975"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBE2J2"},"hgnc":{"alias_symbol":["Ubc6p","NCUBE2"],"prev_symbol":[]},"alphafold":{"accession":"Q8N2K1","domains":[{"cath_id":"3.10.110.10","chopping":"12-177","consensus_level":"high","plddt":96.9395,"start":12,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2K1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2K1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2K1-F1-predicted_aligned_error_v6.png","plddt_mean":84.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBE2J2","jax_strain_url":"https://www.jax.org/strain/search?query=UBE2J2"},"sequence":{"accession":"Q8N2K1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N2K1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N2K1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2K1"}},"corpus_meta":[{"pmid":"9388185","id":"PMC_9388185","title":"Role of Cue1p in ubiquitination and degradation at the ER surface.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9388185","citation_count":323,"is_preprint":false},{"pmid":"11359923","id":"PMC_11359923","title":"Hsp70 molecular chaperone facilitates endoplasmic reticulum-associated protein degradation of cystic fibrosis transmembrane conductance regulator in yeast.","date":"2001","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/11359923","citation_count":221,"is_preprint":false},{"pmid":"9409541","id":"PMC_9409541","title":"Endoplasmic reticulum degradation: reverse protein flow of no return.","date":"1997","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/9409541","citation_count":210,"is_preprint":false},{"pmid":"18812321","id":"PMC_18812321","title":"Degradation of a cytosolic protein requires endoplasmic reticulum-associated degradation machinery.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18812321","citation_count":118,"is_preprint":false},{"pmid":"11278356","id":"PMC_11278356","title":"Endoplasmic reticulum (ER)-associated degradation of T cell receptor subunits. 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membrane-bound ER ubiquitin-conjugating enzyme that works together with Cue1p-assembled Ubc7p to ubiquitinate ERAD substrates; ubiquitination by this pair is a prerequisite for retrograde transport of lumenal substrates out of the ER.\",\n      \"method\": \"Genetic (deletion mutants), biochemical fractionation, ERAD substrate degradation assays in yeast\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods, replicated across multiple subsequent studies\",\n      \"pmids\": [\"9388185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ubc6p/Ubc7p ubiquitin-conjugating enzyme pair recognizes cytosolic degradation signals containing a patch of bulky hydrophobic residues and positively charged residues; ubiquitination of these substrates occurs on the cytosolic face of the ER without prior transfer to the ER lumen, independently of Hrd1p/Der3p and Sec61p retrograde transport.\",\n      \"method\": \"Genetic analysis with deletion mutants (hrd1/der3Δ, sec61-2), fusion protein degradation assays, mutational analysis of degron sequences in yeast\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic backgrounds tested, mutagenesis of signal sequences, clear epistasis results\",\n      \"pmids\": [\"10982838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The tail-anchored ER membrane protein Ubc6p undergoes self-ubiquitination-dependent degradation that requires its own catalytic site cysteine and Cue1p-assembled Ubc7p, but is independent of Ubc1p, Hrd1p/Der3p, Hrd3p, Der1p, and the Sec61p translocon; a membrane-bound degradation intermediate accumulates in proteasome mutants.\",\n      \"method\": \"Genetic deletion mutants, sec61 mutants, pulse-chase degradation assays, proteasome mutant analysis in yeast\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive genetic epistasis across multiple deletion/mutant backgrounds with biochemical readout\",\n      \"pmids\": [\"11406589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Murine UBE2J2 (MmUbc6) is an integral membrane protein anchored via its hydrophobic C-terminal tail to the endoplasmic reticulum; overexpression of catalytically inactive MmUbc7 (not MmUbc6 dominant-negative) significantly delayed ERAD of T cell receptor alpha and CD3-delta subunits, implicating these ER-localized E2s in mammalian ERAD.\",\n      \"method\": \"Immunofluorescence colocalization, dominant-negative overexpression, pulse-chase degradation assays in mammalian cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments plus functional dominant-negative assays, single lab\",\n      \"pmids\": [\"11278356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Two families of mammalian Ubc6p-related proteins (including UBE2J2/NCUBE2) are localized to the ER membrane with the same cytoplasmic-face topology as yeast Ubc6p; expression of wild-type and dominant-negative alleles specifically affects ERAD of TCR-alpha and mutant CFTR, and elevated Ubc6p levels in yeast also affect ERAD, indicating highly conserved function.\",\n      \"method\": \"Subcellular fractionation, topology assays, dominant-negative overexpression, ERAD substrate degradation assays in mammalian cells and yeast\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal methods (localization, topology, functional dominant-negative in both mammalian cells and yeast), two substrates tested\",\n      \"pmids\": [\"12082160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human UBE2J2 (hsUbc6) possesses tail-anchored protein motifs, is localized to the ER, is a functional ubiquitin-conjugating enzyme as shown by in vitro thiol-ester assay, and its expression is induced by the unfolded protein response.\",\n      \"method\": \"In vitro ubiquitin thiol-ester assay, subcellular localization, UPR induction experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay confirms E2 activity, localization confirmed, single lab\",\n      \"pmids\": [\"16720581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UBE2J2 is the primary cellular E2 recruited by the viral E3 ligase mK3 for ERAD; the UBE2J2-mK3 pair preferentially ubiquitinates hydroxylated amino acids (serine/threonine) on ERAD substrates via ester bonds even when lysine residues are present, establishing that noncanonical ubiquitination of hydroxylated residues is physiologically relevant.\",\n      \"method\": \"E2 identification by co-immunoprecipitation/pulldown, in vitro ubiquitination assay with lysine-less substrate mutants, mass spectrometry of ubiquitin linkages\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis and biochemical demonstration of ester bond ubiquitination, multiple substrate variants tested\",\n      \"pmids\": [\"19951915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UBE2J2 is essential for US11-mediated ERAD of HLA class I molecules; TMEM129 (an E3 ligase) together with UBE2J2 (as its cognate E2) is responsible for ubiquitination, dislocation, and degradation of US11-associated MHC-I via a Derlin-1-dependent ERAD complex.\",\n      \"method\": \"Genome-wide shRNA screen, CRISPR forward genetic screen in near-haploid cells, Co-IP, functional degradation assays\",\n      \"journal\": \"Nature communications / PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genetic screens (shRNA and insertional mutagenesis) converged on UBE2J2, functional validation by multiple labs\",\n      \"pmids\": [\"24807418\", \"25030448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UBE2J2 is itself an unstable protein subject to proteasomal degradation; proteasomal inhibitors increase its steady-state levels. This effect requires both catalytic activity and ER localization (disruption of either stabilizes the enzyme), suggesting auto-ubiquitination-linked turnover.\",\n      \"method\": \"Proteasome inhibitor treatment, catalytic mutants, truncation mutants, immunoblot in transfected mammalian cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological and genetic approaches, single lab, no direct ubiquitination demonstrated\",\n      \"pmids\": [\"25083800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBE2J2, in contrast to UBE2J1, is not essential for recovery from transient ER stress; Ube2j1 (not Ube2j2) is the E2 whose phosphorylation by MAPK signaling mediates ER stress recovery, and c-IAP1 preferentially interacts with phosphorylated Ube2j1.\",\n      \"method\": \"Ectopic expression of wild-type and phospho-mutant constructs, cell viability assays, Co-IP in mammalian cells\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional rescue assays and Co-IP, negative result for UBE2J2 role in ER stress recovery is a mechanistically informative distinction, single lab\",\n      \"pmids\": [\"28321712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBE2J2 counteracts US2-induced ERAD by downregulating TRC8 (RNF139) E3 ligase expression; in contrast, UBE2G2 is the crucial E2 for US2-mediated HLA-I degradation, demonstrating distinct roles for different E2s in HCMV immune evasion.\",\n      \"method\": \"Lentiviral CRISPR/Cas9 library screening targeting all human E2 enzymes, functional degradation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale CRISPR screen with functional follow-up, single lab\",\n      \"pmids\": [\"28743740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UBE2J2 functions as the E2 ubiquitin-conjugating enzyme for the E3 ligase CGRRF1 to ubiquitinate the Wnt cargo receptor Evi/Wls for ERAD in the absence of Wnt ligands, thereby regulating Wnt protein secretion.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, ERAD substrate stability assays in mammalian cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with functional ERAD readout plus E2-E3 interaction demonstrated, single lab\",\n      \"pmids\": [\"29378775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UBE2J2 is the primary E2 ubiquitin-conjugating enzyme essential for MARCH6-dependent cholesterol-stimulated degradation of squalene monooxygenase (SQLE), but not for sterol-dependent degradation of HMGCR (which requires UBE2G2), revealing substrate-specific E2 usage in ERAD.\",\n      \"method\": \"CRISPR/Cas9-based screen for ERAD E2 enzymes, catalytic mutant rescue, cholesterol-stimulated degradation assays in multiple human cell types\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen, catalytic mutant dependency, multiple human cell types including hepatic cells, enzymatic activity shown to be required\",\n      \"pmids\": [\"30658189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"US11 recruits Derlin-1, TMEM129, and UBE2J2 to engage FcRn, initiating dislocation of FcRn from the ER to the cytosol and its degradation, thereby inhibiting IgG-FcRn binding and IgG transport.\",\n      \"method\": \"Co-immunoprecipitation, ERAD substrate degradation assays, functional IgG transcytosis assays in mammalian cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP complex formation and functional degradation demonstrated, single lab\",\n      \"pmids\": [\"31289263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBE2J2, together with UBE2K and UBE2N, mediates K11-, K48-, and K63-linked ubiquitylation of EVI/WLS, independently of E3 ligases HRD1 and GP78; ERLIN2 links EVI/WLS to the ubiquitylation machinery.\",\n      \"method\": \"RNAi screen, Co-IP, ubiquitin linkage analysis, E3 ligase independence assays in mammalian cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen plus Co-IP, ubiquitin linkage typing, single lab\",\n      \"pmids\": [\"34406391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ube2j2 functions cooperatively with Ube2k as E2 ubiquitin-conjugating enzymes with the E3 ligase March5 at the mitochondria; depletion of Ube2j2 sensitizes AML cells to Venetoclax specifically in the presence of March5, and March5 controls Noxa levels to regulate Bax-Mcl1 interactions in the apoptosis pathway.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screens, genetic knockouts, CRISPR epistasis screens in mouse AML cells\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screens with epistasis and functional apoptosis readouts, single lab\",\n      \"pmids\": [\"36973350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"X-ray crystallography and MD simulations of Ubc6/UBE2J2 revealed a two-layered mechanism for serine ubiquitination: (1) rearrangement of the active site enhances E2-Ub thioester reactivity toward weak nucleophiles; (2) a conserved histidine in Ubc6/UBE2J2 activates substrate serine via general base catalysis. RING-type E3 ligases further increase serine selectivity via an allosteric mechanism requiring specific positioning of the ubiquitin tail at the E2 active site.\",\n      \"method\": \"X-ray crystallography, molecular dynamics simulations, in vitro reconstitution ubiquitination assays, active-site mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus MD simulations plus reconstitution and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"39533056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2J2 acts as a membrane lipid sensor in ERAD: in loosely packed membranes, its transmembrane domain associates with membrane lipids in a way that impedes ubiquitin loading (rendering it inactive), while tighter lipid packing promotes an active conformation and interaction with E1. This activity directs ubiquitin transfer by multiple E3 ligases (RNF145, MARCHF6, RNF139) targeting themselves and the substrate squalene monooxygenase.\",\n      \"method\": \"In vitro reconstitution with purified ERAD factors, lipid-composition modulation of proteoliposomes, ubiquitination assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — fully reconstituted system with purified components and defined lipid compositions, multiple E3 ligase partnerships demonstrated\",\n      \"pmids\": [\"41068091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2J2 is essential for male meiosis in mice; Ube2j2 knockout male mice are azoospermic with spermatocytes arrested at mid-pachytene stage, exhibiting unstable homologous recombination intermediate complexes that fail to form crossovers, and loss of a broad set of meiosis- and chromosome segregation-associated proteins.\",\n      \"method\": \"Knockout mouse model, histology, immunofluorescence of HR markers (e.g., MLH1, RPA), proteomics of spermatocytes\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined cellular phenotype and proteomic characterization, single lab, mechanism of action (beyond ERAD context) not fully resolved\",\n      \"pmids\": [\"40686610\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBE2J2 (human ortholog of yeast Ubc6p) is a tail-anchored, ER membrane-localized E2 ubiquitin-conjugating enzyme whose active site uniquely enables both canonical lysine ubiquitination and noncanonical serine/threonine ester-bond ubiquitination through a histidine-mediated general base catalysis mechanism; it functions as the primary E2 for multiple ERAD E3 ligases (including TMEM129, MARCH6/MARCHF6, CGRRF1, RNF145, and RNF139) to ubiquitinate diverse substrates (MHC-I, squalene monooxygenase, EVI/WLS, FcRn), and additionally acts as a sensor for membrane lipid saturation—with its transmembrane domain toggling between active and inactive states depending on lipid packing—thereby coupling ER membrane homeostasis to ERAD activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBE2J2 is a tail-anchored, ER membrane-localized E2 ubiquitin-conjugating enzyme that serves as a central conjugating component of endoplasmic-reticulum-associated degradation (ERAD), conserved from its yeast ortholog Ubc6p, which ubiquitinates ERAD substrates on the cytosolic face of the ER as a prerequisite for their retrotranslocation and proteasomal degradation [#0, #4]. It is anchored to the ER via a hydrophobic C-terminal tail with cytosolic-facing catalytic topology, is a functional E2 by in vitro thiol-ester assay, and is induced by the unfolded protein response [#3, #5]. A defining feature of UBE2J2 is its capacity for noncanonical ubiquitination: it ubiquitinates serine/threonine residues through ester bonds even when lysines are available, a chemistry enabled by an active-site rearrangement that boosts E2-Ub thioester reactivity and a conserved histidine acting as a general base to activate the substrate hydroxyl, with RING E3 ligases sharpening serine selectivity allosterically [#6, #16]. UBE2J2 functions as the cognate E2 for a broad set of ER-membrane E3 ligases—TMEM129, MARCH6/MARCHF6, CGRRF1, RNF145, and RNF139—to ubiquitinate substrates including MHC class I, FcRn, the Wnt cargo receptor EVI/WLS, and squalene monooxygenase, with substrate- and ligase-specific E2 usage that distinguishes it from UBE2G2 [#7, #11, #12, #13, #17]. It is exploited by viral E3 ligases (mK3, US11) to drive immune-evasion degradation of MHC-I and FcRn [#6, #7, #13]. Beyond catalysis, UBE2J2 acts as a membrane lipid-packing sensor whose transmembrane domain toggles between ubiquitin-loading-competent and inactive states with lipid order, coupling ER membrane homeostasis to ERAD output [#17]. UBE2J2 is itself an unstable, catalysis- and ER-localization-dependent substrate of proteasomal turnover [#8], and is required for male meiotic progression in mice, where its loss arrests spermatocytes at mid-pachytene with defective crossover formation [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that an ER membrane-bound E2 (yeast Ubc6p, ortholog of UBE2J2) is a required upstream actor in ERAD, linking ubiquitination to retrograde extraction of misfolded substrates.\",\n      \"evidence\": \"Genetic deletion mutants and ERAD substrate degradation assays in yeast\",\n      \"pmids\": [\"9388185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the mammalian ortholog's role\", \"Site of ubiquitin attachment and substrate range unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved where ubiquitination occurs by showing the Ubc6p/Ubc7p pair acts on cytosolic degrons on the ER's cytosolic face, independent of luminal transfer and Sec61/Hrd1.\",\n      \"evidence\": \"Genetic epistasis and degron mutagenesis in yeast\",\n      \"pmids\": [\"10982838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate-recognition determinants in mammals untested\", \"E3 ligase partners for these degrons not fully mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined UBE2J2 as a tail-anchored ER integral membrane protein in mammals and implicated ER-localized E2s in mammalian ERAD of TCR and CD3 subunits.\",\n      \"evidence\": \"Immunofluorescence, dominant-negative overexpression, pulse-chase in mammalian cells; yeast self-ubiquitination/turnover assays\",\n      \"pmids\": [\"11278356\", \"11406589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct catalytic requirement of UBE2J2 (vs UBE2J1/Ubc7) for specific substrates not isolated\", \"Cognate E3 ligases in mammals unidentified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Confirmed conserved cytoplasmic-face topology and ERAD function of mammalian Ubc6p-related E2s across species, generalizing the role to multiple substrates (TCR-alpha, mutant CFTR).\",\n      \"evidence\": \"Fractionation, topology assays, dominant-negative ERAD assays in mammalian cells and yeast\",\n      \"pmids\": [\"12082160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous loss-of-function effects not tested\", \"Specific E2-E3 pairings undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Confirmed human UBE2J2 is a bona fide functional E2 with tail-anchor motifs and UPR-inducible expression, embedding it in the ER stress response.\",\n      \"evidence\": \"In vitro thiol-ester assay, localization, UPR induction in mammalian cells\",\n      \"pmids\": [\"16720581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate or E3 partner defined in this study\", \"Single-lab in vitro activity\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovered that UBE2J2 catalyzes noncanonical ester-bond ubiquitination of serine/threonine even in the presence of lysines, redefining the chemistry of ubiquitin transfer it can perform.\",\n      \"evidence\": \"E2 pulldown, in vitro ubiquitination with lysine-less substrates, mass spectrometry of linkages (viral E3 mK3)\",\n      \"pmids\": [\"19951915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ester-bond catalysis not yet resolved\", \"Generality across cellular E3 ligases untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified UBE2J2 as the cognate E2 for the E3 TMEM129 in US11-driven MHC-I dislocation, establishing a specific E2-E3 axis in viral immune evasion.\",\n      \"evidence\": \"Genome-wide shRNA and CRISPR haploid screens, Co-IP, degradation assays\",\n      \"pmids\": [\"24807418\", \"25030448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same axis operates on endogenous MHC-I turnover unclear\", \"Role of ester vs lysine linkage on this substrate not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed UBE2J2 is itself an unstable protein turned over by the proteasome in a manner dependent on its catalytic activity and ER localization, implying auto-regulatory turnover.\",\n      \"evidence\": \"Proteasome inhibitors, catalytic and truncation mutants, immunoblot\",\n      \"pmids\": [\"25083800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct auto-ubiquitination not demonstrated\", \"Responsible E3, if any, not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished UBE2J2 from its paralog UBE2J1 by showing UBE2J2 is dispensable for ER stress recovery and is not the MAPK-phosphorylated/c-IAP1-interacting E2, sharpening functional non-redundancy.\",\n      \"evidence\": \"Phospho-mutant constructs, viability assays, Co-IP in mammalian cells\",\n      \"pmids\": [\"28321712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UBE2J2 is regulated by any post-translational signal unknown\", \"Negative result; single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated E2 selectivity in viral ERAD, with UBE2J2 modulating TRC8/RNF139 levels while UBE2G2 drives US2-mediated HLA-I degradation, reinforcing E2-specific routing.\",\n      \"evidence\": \"Genome-scale CRISPR screen of all E2s with functional follow-up\",\n      \"pmids\": [\"28743740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which UBE2J2 downregulates TRC8 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the substrate/E3 repertoire by establishing UBE2J2 as the E2 for CGRRF1-mediated EVI/WLS degradation (Wnt secretion control) and for MARCH6-dependent SQLE degradation (cholesterol-regulated sterol metabolism), with substrate-specific E2 usage versus UBE2G2.\",\n      \"evidence\": \"RNAi/CRISPR screens, Co-IP, catalytic-mutant rescue, ERAD stability assays in multiple human cell types\",\n      \"pmids\": [\"29378775\", \"30658189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SQLE/EVI ubiquitination uses ester linkages unresolved\", \"How E3 selection partitions substrates not mechanistically explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed UBE2J2 within a Derlin-1/TMEM129 complex drives FcRn dislocation and degradation, providing a functional consequence (blockade of IgG transport) for its ERAD activity.\",\n      \"evidence\": \"Co-IP, degradation and IgG transcytosis assays in mammalian cells (US11 context)\",\n      \"pmids\": [\"31289263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (non-viral) FcRn regulation not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed UBE2J2 can build K11/K48/K63 linkages on EVI/WLS cooperatively with UBE2K and UBE2N independently of HRD1/GP78, with ERLIN2 bridging substrate to machinery, broadening its linkage and partner range.\",\n      \"evidence\": \"RNAi screen, Co-IP, ubiquitin linkage typing, E3-independence assays\",\n      \"pmids\": [\"34406391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with CGRRF1-dependent EVI degradation unclear\", \"Direct E3 catalyzing these linkages not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended UBE2J2 function beyond the ER by showing it acts with UBE2K and the mitochondrial E3 MARCH5 to regulate Noxa/Bax-Mcl1 apoptotic signaling, modulating Venetoclax sensitivity in AML.\",\n      \"evidence\": \"Genome-wide CRISPR and epistasis screens, knockouts, apoptosis readouts in mouse AML cells\",\n      \"pmids\": [\"36973350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial vs ER pool of UBE2J2 not distinguished\", \"Direct mitochondrial substrate of UBE2J2 not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural and mechanistic basis for serine ubiquitination: active-site rearrangement enhances thioester reactivity and a conserved histidine acts as a general base, with RING E3s adding allosteric serine selectivity.\",\n      \"evidence\": \"X-ray crystallography, MD simulations, in vitro reconstitution and active-site mutagenesis\",\n      \"pmids\": [\"39533056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell contribution of ester vs lysine linkages per substrate not quantified\", \"Which physiological substrates are serine-ubiquitinated remains to be mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated UBE2J2 is a membrane lipid-packing sensor whose transmembrane domain toggles ubiquitin-loading competence with lipid order, coupling ER membrane homeostasis to ERAD by multiple E3 ligases (RNF145, MARCHF6, RNF139).\",\n      \"evidence\": \"Reconstitution with purified ERAD factors and defined-lipid proteoliposomes, ubiquitination assays\",\n      \"pmids\": [\"41068091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell evidence that physiological lipid changes toggle activity not shown\", \"How lipid sensing integrates with E3 selection unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a physiological requirement for UBE2J2 in male meiosis, with knockout mice azoospermic due to mid-pachytene arrest, unstable recombination intermediates, and failed crossover formation.\",\n      \"evidence\": \"Knockout mouse model, histology, HR-marker immunofluorescence, spermatocyte proteomics\",\n      \"pmids\": [\"40686610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between UBE2J2 ubiquitination activity and recombination not defined\", \"Whether ERAD substrates mediate the meiotic phenotype unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown which endogenous substrates are serine/ester-ubiquitinated in cells, how lipid sensing and E3 selection are integrated in vivo, and what molecular pathway connects UBE2J2 catalysis to meiotic recombination.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in-cell quantification of ester vs lysine linkage per substrate\", \"Mechanism coupling ERAD/ubiquitination to meiotic crossover formation undefined\", \"Physiological lipid triggers of the sensor not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 16, 12, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5, 6, 16]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3, 4, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 7, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 10, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"Derlin-1/TMEM129/UBE2J2 ERAD dislocation complex\"\n    ],\n    \"partners\": [\n      \"TMEM129\",\n      \"MARCHF6\",\n      \"CGRRF1\",\n      \"RNF145\",\n      \"RNF139\",\n      \"MARCH5\",\n      \"UBE2K\",\n      \"ERLIN2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}