{"gene":"UBQLN1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"PLIC-1 (UBQLN1) directly interacts with GABA(A) receptor subunits, is enriched at inhibitory synapses and associated with subsynaptic membranes, facilitates GABA(A) receptor cell surface expression without affecting internalization rate, and enhances stability of intracellular GABA(A) receptor subunits to increase receptors available for plasma membrane insertion.","method":"Co-immunoprecipitation, immunolocalization (confocal microscopy/electron microscopy), cell surface expression assays, receptor internalization assays in neurons","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional cellular readouts (surface expression, internalization rate), replicated and extended in subsequent study (PMID:18467327)","pmids":["11528422"],"is_preprint":false},{"year":2008,"finding":"Plic-1 (UBQLN1) increases the stability of GABA(A) receptor subunits within the endoplasmic reticulum, increases poly-ubiquitinated receptor subunit abundance, and elevates cell surface expression by selectively increasing rates of membrane insertion.","method":"Recombinant and neuronal preparations, pulse-chase and stability assays, cell surface biotinylation, poly-ubiquitination detection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ER stability, ubiquitination, membrane insertion rate) in both recombinant and neuronal systems, corroborates and extends PMID:11528422","pmids":["18467327"],"is_preprint":false},{"year":1999,"finding":"XDRP1 (Xenopus ortholog of UBQLN1) was identified as a cyclin A-binding protein via two-hybrid screen; it binds cyclin A1 and A2 (but not B-type cyclins) through its N-terminal UBL domain, requiring residues 130–160 of cyclin A1; bacterially expressed XDRP1 inhibits Ca2+-induced degradation of cyclin A but not cyclin B in frog egg extract; injection of XDRP1 into fertilized Xenopus eggs blocks embryonic cell division.","method":"Yeast two-hybrid, in vitro binding assays, cell-free degradation assay in frog egg extract, Xenopus microinjection","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of cyclin A degradation inhibition plus mutagenesis-level domain mapping plus in vivo injection phenotype, single study with multiple orthogonal methods","pmids":["10487753"],"is_preprint":false},{"year":2006,"finding":"Two isoforms of Xenopus XDRP1 (XDRP1L and XDRP1S) differ in their UBL domain; both bind polyubiquitinated proteins via their UBA domains, but only XDRP1L binds the proteasome via its UBL domain, whereas XDRP1S (with a truncated UBL) fails to bind the proteasome and instead binds monomeric cyclin A and prevents its degradation.","method":"In vitro binding assays, pulldown with polyubiquitinated proteins, proteasome binding assays, cyclin A degradation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with domain-level analysis, single lab, single study","pmids":["17027914"],"is_preprint":false},{"year":2003,"finding":"PLIC-1 (UBQLN1) inhibits Gβγ-dependent cell signaling (but not Gs-mediated adenylyl cyclase activation) by directly associating with Gβγ; this interaction does not require the UBL or UBA domains of PLIC-1; PLIC-1 co-localizes with G proteins in lamellae and pseudopods and inhibits SDF-1α-induced phospholipase C activation, CXCR4 internalization, and cell migration.","method":"GST pulldown, co-immunoprecipitation, confocal colocalization, chemotaxis assays, phospholipase C activation assay, adenylyl cyclase assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown and Co-IP with domain mapping, multiple functional readouts (PLC, migration, internalization), single lab","pmids":["14662753"],"is_preprint":false},{"year":2006,"finding":"The UBL domain of PLIC-1 (UBQLN1) is required for aggresome formation; PLIC-1 binds UIM-containing proteins ataxin-3, HSJ1a, and EPS15 via its UBL domain; PLIC-1 and EPS15 localize to perinuclear aggresomes; polyQ expression enhances PLIC-1–EPS15 interaction; PLIC-1 knockdown reduces aggresome formation; a dominant-negative PLIC-1(ΔUBL) blocks polyQ transport to aggresomes and disrupts EPS15 association with aggregates; PLIC-1 is upregulated by arsenite-induced protein misfolding.","method":"Co-immunoprecipitation, RNAi knockdown, dominant-negative overexpression, immunofluorescence/confocal microscopy, polyQ disease model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mutant, RNAi loss-of-function, dominant-negative, multiple binding partners identified, single lab with multiple orthogonal methods","pmids":["17082820"],"is_preprint":false},{"year":2011,"finding":"PLIC-1 (UBQLN1) interacts with the TIR domain of TLR4 (via yeast two-hybrid) and with TRIF (confirmed by Co-IP and GST pulldown); PLIC-1 strongly suppresses TLR3-TRIF-dependent IFN-β promoter activation; PLIC-1 and TRIF co-localize with autophagosome marker LC3 in punctate structures; PLIC-1 overexpression decreases TRIF protein abundance in a nocodazole-sensitive manner; PLIC-1 knockdown by shRNA enhances TLR3 activation.","method":"Yeast two-hybrid, Co-IP, GST pulldown, luciferase reporter assay, shRNA knockdown, confocal microscopy, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and GST pulldown plus loss-of-function with specific reporter readout, single lab","pmids":["21695056"],"is_preprint":false},{"year":2010,"finding":"UBQLN1 interacts with SPEM1 (identified by yeast two-hybrid) and both proteins co-localize to the manchette of elongating spermatids, implicating UBQLN1 in regulation of protein ubiquitination during spermiogenesis.","method":"Yeast two-hybrid, immunofluorescence co-localization","journal":"Molecular and cellular endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid and co-localization only, no functional mechanistic follow-up for UBQLN1 specifically","pmids":["20558241"],"is_preprint":false},{"year":1997,"finding":"DA41 (UBQLN1) interacts with the EGF-like protein S(1-5) through amino acids 155–232 of DA41, identified by yeast two-hybrid.","method":"Yeast two-hybrid, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only, no in-cell validation of interaction","pmids":["9268694"],"is_preprint":false},{"year":2017,"finding":"The first two STI domains of UBQLN1 are critical for binding to the substrate BCLb (and similarly to IGF1R and ESYT2); interaction of UBQLN1 with BCLb is independent of BCLb ubiquitination, but interaction with ubiquitin via the UBA domain is required for substrate stabilization; UBL-mediated interactions (e.g., with PSMD4 and BAG6) do not result in substrate stabilization by UBQLN1. Thus, substrate fate (stabilization vs. degradation) is determined by the domain of UBQLN1 mediating substrate contact.","method":"Co-immunoprecipitation, domain deletion/mutation constructs, proteasome and ubiquitin-binding assays, Western blot","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level mapping with multiple substrates and orthogonal readouts (stabilization, ubiquitin binding), single lab","pmids":["28075048"],"is_preprint":false},{"year":2012,"finding":"The missense mutation UBQLN1-E54D causes cytosolic aggregate formation and mislocalized TDP-43, and impairs degradation of ubiquitinated proteins through the proteasome in vitro, demonstrating that this mutation disrupts UPS function.","method":"In vitro functional studies, immunofluorescence, ubiquitinated protein degradation assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional UPS degradation assay plus aggregate/TDP-43 localization, single lab, single mutant","pmids":["22766032"],"is_preprint":false},{"year":2021,"finding":"Upregulated UBQLN1 in sorafenib-resistant HCC cells induces degradation of PGC1β in a ubiquitination-independent manner, attenuating mitochondrial biogenesis and ROS production.","method":"Co-immunoprecipitation, Western blot, mitochondrial functional assays (oxygen consumption rate, mitochondrial DNA content), gain/loss-of-function experiments","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection with Co-IP, functional mitochondrial assays, and ubiquitination-independence demonstrated, single lab","pmids":["34001851"],"is_preprint":false},{"year":2023,"finding":"CD36 acts as a bridge molecule linking UBQLN1 to SNARE proteins (STX17, SNAP29, VAMP8) at the lysosome, promoting their proteasomal degradation in a UBQLN1-dependent manner, thereby impairing autophagosome-lysosome fusion.","method":"Co-immunoprecipitation, knockout and overexpression in mice and cells, autophagic flux assays, Western blot","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating ternary complex, KO rescue experiments, functional readout (autophagosome-lysosome fusion), single lab","pmids":["37014234"],"is_preprint":false},{"year":2023,"finding":"The E6AP AZUL domain binds transiently to the UBA domain of UBQLN1/2; NOE spectroscopy identified direct intermolecular contacts; an AlphaFold2-Multimer model of the AZUL:UBA complex was generated; an oligomerization domain (UBAA) adjacent to the UBA is α-helical and is allosterically reconfigured by AZUL binding; E6AP interacts with UBQLN1/2 in cellulo and E6AP AZUL is recruited to UBQLN2 condensates in vitro.","method":"NMR (NOE spectroscopy, transfer NOE), AlphaFold2-Multimer structure prediction, in vitro condensate assay, co-immunoprecipitation in cells","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR with intermolecular NOE restraints plus structural modeling plus cellular Co-IP, multiple orthogonal methods in single study","pmids":["36827983"],"is_preprint":false},{"year":2023,"finding":"UBQLN1 interacts with RPA1 and shuttles it off from the replication fork; UBQLN1 deficiency retains RPA1 at the replication fork, hinders replication, causes cell cycle arrest, genome instability, and rapid telomere shortening (particularly in telomere regions with G-rich sequences prone to replication stress).","method":"Co-immunoprecipitation, RPA1 ChIP at replication forks, UBQLN1 knockdown with telomere length measurement, cell cycle assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional knockdown with specific genomic readout (telomere shortening, replication fork assay), single lab","pmids":["37463174"],"is_preprint":false},{"year":2023,"finding":"Full-length UBQLN1, UBQLN2, and UBQLN4 exhibit distinct phase separation behaviors in vitro; the short N-terminal disordered regions inhibit phase separation via electrostatic interactions; UBQLN1 does not phase separate with a temperature dependence (unlike UBQLN2, whose temperature-dependent behavior requires its unique proline-rich region absent in UBQLN1).","method":"In vitro phase separation assays with full-length proteins and charge variant/truncation constructs, biophysical characterization","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple deletion and charge variants, comparative analysis across family members, single lab","pmids":["38041404"],"is_preprint":false},{"year":2000,"finding":"Overexpression of DA41 (UBQLN1) in v-Ha-ras-transformed 3Y1 cells suppresses cell growth and reduces CDK2 kinase activity without altering CDK2 protein levels, indicating a role in cell cycle regulation.","method":"Stable transfection/overexpression, growth assays, soft agar colony formation, CDK2 kinase activity assay, Western blot","journal":"Japanese journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional overexpression with CDK2 activity assay readout, single lab, single study","pmids":["11050468"],"is_preprint":false},{"year":2024,"finding":"Foxc1 functions as a transcriptional activator of Ubqln1; Sirt1 promotes Foxc1 expression by deacetylating Ezh2 and inhibiting its repressive activity on Foxc1; the Sirt1/Foxc1/Ubqln1 axis regulates proteostasis (ubiquitinated protein aggregation) and neuronal survival during cerebral ischemia/reperfusion injury.","method":"Co-IP, ChIP, dual-luciferase reporter assay, siRNA knockdown, MCAO/R and OGD/R models","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus dual-luciferase plus Co-IP for pathway placement, single lab","pmids":["38452414"],"is_preprint":false},{"year":2020,"finding":"UBQLN1 knockdown reduces p53 protein levels through activation of autophagy (not proteasomal degradation); inhibition of autophagy restores p53 levels in UBQLN1-KD cells; UBQLN1 KD inhibits mTOR and its downstream S6K phosphorylation.","method":"siRNA knockdown, autophagy inhibitor treatment, proteasome activity assay, MTT, BrdU, TUNEL assays, Western blot","journal":"Journal of thoracic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with pharmacological rescue and proteasome activity assay, single lab, single study","pmids":["33209421"],"is_preprint":false},{"year":2024,"finding":"UBQLN1 interacts with SNARE proteins and promotes their ubiquitin-mediated proteasomal degradation; its STI domain mediates binding to substrate GPX4 and stabilizes it (demonstrated in HCC); separately, UBQLN1 was shown to stabilize substrates through STI-domain interaction independent of substrate ubiquitination.","method":"Co-immunoprecipitation, domain deletion experiments, Western blot, functional ferroptosis assays","journal":"MedComm","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with domain implication, single study, limited mechanistic follow-up for UBQLN1 STI-GPX4 interaction specifically","pmids":["41287824"],"is_preprint":false},{"year":2024,"finding":"UBQLN1 mediates ubiquitin-dependent degradation of Pgm1; Sec13 competes with UBQLN1 for binding to Pgm1, thereby inhibiting UBQLN1-mediated Pgm1 ubiquitination and stabilizing Pgm1 to promote glycolysis.","method":"Co-immunoprecipitation demonstrating ternary complex (Sec13–Pgm1–Ubqln1), Ubqln1 overexpression/knockdown, Western blot for Pgm1 stability, ubiquitination assay","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with overexpression/KD, single lab, ubiquitination assay but abstract-level detail only","pmids":["39159700"],"is_preprint":false},{"year":2026,"finding":"Lipotoxic stress induces O-GlcNAcylation at T277 of UBQLN1 by OGT, which competitively inhibits phosphorylation at the same site and reduces ubiquitin-mediated degradation of UBQLN1, stabilizing it; UBQLN1 in hepatocytes regulates MVB–lysosome fusion via LAMP1, promoting sEV secretion; sEV-carried UBQLN1 degrades the V-ATPase subunit ATP6V1B2 through E54D-dependent ubiquitin ligase activity, inhibiting lysosomal acidification and mitophagy in hepatic stellate cells.","method":"Co-IP, site-directed mutagenesis (T277), O-GlcNAc and phosphorylation detection, LAMP1 interaction assays, lysosomal acidification assay, hepatocyte-specific Ubqln1/Ogt knockdown in MASH mice","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM with mutagenesis plus functional downstream assays, multiple orthogonal methods, single lab","pmids":["41795680"],"is_preprint":false},{"year":2026,"finding":"MYDGF competitively binds UBQLN1 at its STI1-4 domain, blocking UBQLN1-mediated ERAD recognition and degradation of LCN2, thereby stabilizing LCN2 and suppressing ferroptosis in gastric cancer under hypoxia.","method":"Co-immunoprecipitation, domain competition assay, LCN2 stability assay, ferroptosis assays in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with competitive domain binding plus functional ferroptosis readout, single lab","pmids":["41942632"],"is_preprint":false},{"year":2026,"finding":"UBQLN1 promotes ubiquitin-mediated degradation of SIKE, activating the p38 MAPK pathway to drive lipid accumulation in hepatocytes during MASH; genetic knockdown of UBQLN1 reduces SIKE degradation and suppresses p38 MAPK signaling, hepatic steatosis, and fibrosis.","method":"LC-MS/MS proteomics, transcriptomics, Co-IP, UBQLN1 knockdown in MASH mouse models and hepatocytes, Western blot","journal":"Journal of nanobiotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and KD with pathway readout, abstract-level detail only, single lab","pmids":["41814315"],"is_preprint":false},{"year":2015,"finding":"Disruption of PLIC-1 binding to GABA(A) receptors (by the PePα peptide) decreases miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal pyramidal neurons, while lentiviral overexpression of Plic-1 increases mIPSCs; these effects are blocked by the GABA(A)R inhibitor picrotoxin, confirming that Plic-1 regulates inhibitory synaptic transmission specifically through GABA(A) receptors.","method":"Intrahippocampal peptide injection, lentiviral overexpression, whole-cell patch-clamp electrophysiology (mIPSC recording) in rat and mouse models","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiological readout with pharmacological control (picrotoxin), in vivo and in vitro models, single lab","pmids":["26415648"],"is_preprint":false}],"current_model":"UBQLN1 (also known as PLIC-1, XDRP1, DA41) is a ubiquitin-like/ubiquitin-associated shuttle protein whose UBL domain engages the proteasome and UIM-containing proteins (including proteasomal subunit S5a/PSMD4, ataxin-3, EPS15, and the E3 ligase E6AP via its AZUL domain), whose STI chaperone-like domains bind and determine the fate of diverse substrates (BCLb, IGF1R, GPX4, LCN2, PGC1β, SNARE proteins, Pgm1), and whose UBA domain binds polyubiquitinated cargo; UBQLN1 stabilizes GABA(A) receptors in the ER and promotes their synaptic surface insertion, inhibits Gβγ-dependent G-protein signaling by direct association, facilitates aggresome formation via UBL–UIM interactions with EPS15, suppresses TLR3-TRIF innate immune signaling by reducing TRIF abundance, promotes proteasomal degradation of SNARE proteins (impairing autophagosome–lysosome fusion when upregulated), interacts with RPA1 to facilitate replication fork progression and telomere maintenance, undergoes O-GlcNAcylation at T277 (by OGT) that stabilizes it, and can modulate cell cycle progression (reducing CDK2 activity) and mitochondrial biogenesis (through ubiquitination-independent PGC1β degradation)."},"narrative":{"mechanistic_narrative":"UBQLN1 (PLIC-1, XDRP1, DA41) is a multidomain ubiquitin-like/ubiquitin-associated shuttle protein that controls the fate of diverse client proteins by coupling substrate recognition to the proteasome and to autophagy/lysosomal pathways [PMID:17082820, PMID:28075048]. Its N-terminal UBL domain engages UIM-containing partners including ataxin-3, HSJ1a, and EPS15 and is required for transport of polyQ aggregates to perinuclear aggresomes, while its UBA domain binds polyubiquitinated cargo [PMID:17082820, PMID:17027914]; the E6AP AZUL domain binds transiently to the UBA domain, allosterically reconfiguring an adjacent oligomerization element [PMID:36827983]. Substrate destiny is set by which UBQLN1 domain contacts the client: STI-domain binding (to substrates such as BCLb, IGF1R, GPX4, and LCN2) plus UBA-mediated ubiquitin engagement stabilizes substrates, whereas UBL-mediated interactions route them toward turnover [PMID:28075048, PMID:41942632]. Through these activities UBQLN1 governs proteostasis and protein quality control: the disease-associated E54D mutation impairs proteasomal degradation of ubiquitinated proteins and causes cytosolic aggregation with TDP-43 mislocalization [PMID:22766032], and a Sirt1/Foxc1 transcriptional axis upregulates UBQLN1 to protect neurons during ischemia/reperfusion [PMID:38452414]. UBQLN1 also has substrate-specific regulatory roles in neurons, where it directly binds GABA(A) receptor subunits, stabilizes them in the ER, and increases their rate of surface insertion to enhance inhibitory synaptic transmission [PMID:11528422, PMID:18467327, PMID:26415648]; in cell-cycle and growth control, where its UBL domain binds cyclin A and inhibits its degradation and its overexpression suppresses CDK2 activity [PMID:10487753, PMID:11050468]; and in Gβγ-dependent G-protein signaling, which it inhibits by direct, UBL/UBA-independent association with Gβγ [PMID:14662753]. More recent work places UBQLN1 in autophagy and metabolic disease, promoting proteasomal degradation of SNARE proteins (STX17, SNAP29, VAMP8) via a CD36 bridge to impair autophagosome–lysosome fusion [PMID:37014234], degrading PGC1β in a ubiquitination-independent manner to limit mitochondrial biogenesis [PMID:34001851], and being stabilized by OGT-dependent O-GlcNAcylation at T277 in a lipotoxic, MASH-relevant context [PMID:41795680]. UBQLN1 additionally shuttles RPA1 off replication forks to support fork progression and telomere maintenance [PMID:37463174].","teleology":[{"year":1999,"claim":"Established the first functional handle on the protein by identifying it as a cyclin A-binding factor whose UBL domain selectively blocks cyclin A degradation and arrests cell division.","evidence":"Yeast two-hybrid, in vitro cyclin degradation in frog egg extract, and Xenopus microinjection","pmids":["10487753"],"confidence":"High","gaps":["Did not connect cyclin A protection to a defined proteasome-targeting mechanism","Human ortholog function not yet demonstrated"]},{"year":2001,"claim":"Defined a neuronal substrate-stabilizing role, showing the protein binds GABA(A) receptor subunits and increases surface receptor availability without altering internalization.","evidence":"Co-IP, immunolocalization, and cell-surface/internalization assays in neurons","pmids":["11528422"],"confidence":"High","gaps":["Mechanism of how binding promotes insertion not resolved at this stage","Domain requirement on UBQLN1 not mapped"]},{"year":2003,"claim":"Revealed a ubiquitin-independent signaling function: direct association with Gβγ inhibits chemokine-driven PLC activation, receptor internalization, and migration, separating signaling roles from the UBL/UBA domains.","evidence":"GST pulldown, Co-IP, chemotaxis and PLC assays","pmids":["14662753"],"confidence":"High","gaps":["Structural basis of Gβγ binding unknown","Physiological context of this inhibition not defined in vivo"]},{"year":2006,"claim":"Connected the protein to protein quality control by demonstrating its UBL domain recruits UIM proteins (ataxin-3, HSJ1a, EPS15) to drive polyQ aggresome formation.","evidence":"Co-IP, RNAi, dominant-negative ΔUBL, and confocal microscopy in a polyQ model","pmids":["17082820"],"confidence":"High","gaps":["Whether aggresome targeting reflects degradation or sequestration not resolved","Endogenous regulation of partner selection unclear"]},{"year":2008,"claim":"Mechanistically refined the GABA(A) receptor role, showing ER stabilization and increased poly-ubiquitinated subunit abundance accelerate membrane insertion.","evidence":"Pulse-chase, biotinylation, and ubiquitination assays in recombinant and neuronal systems","pmids":["18467327"],"confidence":"High","gaps":["Identity of the ubiquitin ligase acting on receptor subunits not established"]},{"year":2011,"claim":"Extended quality-control function to innate immunity, showing the protein suppresses TLR3-TRIF IFN-β signaling by lowering TRIF abundance.","evidence":"Y2H, Co-IP, GST pulldown, luciferase reporter, shRNA knockdown, and LC3 colocalization","pmids":["21695056"],"confidence":"Medium","gaps":["Whether TRIF loss is proteasomal or autophagic not fully resolved","Single lab"]},{"year":2012,"claim":"Linked the protein directly to neurodegenerative disease mechanism, showing the E54D mutation aggregates, mislocalizes TDP-43, and impairs proteasomal degradation of ubiquitinated substrates.","evidence":"In vitro UPS degradation assay and immunofluorescence of a single mutant","pmids":["22766032"],"confidence":"Medium","gaps":["Single mutant in vitro only","Causality in a defined Mendelian disease not established here"]},{"year":2017,"claim":"Resolved the central logic of substrate fate, showing STI domains contact substrates (BCLb, IGF1R, ESYT2) and that UBA-ubiquitin binding stabilizes them while UBL interactions (PSMD4, BAG6) do not.","evidence":"Co-IP with domain deletion/mutation and ubiquitin/proteasome binding assays","pmids":["28075048"],"confidence":"Medium","gaps":["Why some STI-bound substrates are stabilized and others degraded not fully delineated","Single lab"]},{"year":2023,"claim":"Broadened roles into autophagy, replication, and structural understanding: a CD36 bridge targets SNARE proteins for degradation impairing autophagosome-lysosome fusion; the protein shuttles RPA1 off forks for telomere maintenance; and NMR/AF2 mapped E6AP AZUL binding to the UBA domain.","evidence":"Co-IP/KO autophagic flux assays; RPA1 ChIP and telomere length; NMR NOE and AlphaFold2-Multimer with cellular Co-IP","pmids":["37014234","37463174","36827983"],"confidence":"High","gaps":["Functional consequence of E6AP-UBA binding for substrate handling unknown","Whether CD36-SNARE and RPA1 roles intersect with canonical proteostasis unclear"]},{"year":2024,"claim":"Placed the protein in metabolic and disease networks, with substrate-specific control of GPX4, Pgm1, and SIKE, and an upstream Sirt1/Foxc1 transcriptional axis governing neuronal proteostasis.","evidence":"Co-IP, domain deletion, ubiquitination assays, ChIP/luciferase, and knockdown in disease models","pmids":["38452414","41287824","39159700","41814315"],"confidence":"Medium","gaps":["Several substrate findings are abstract-level or single-study","Whether degradation routes are proteasomal vs lysosomal varies by substrate"]},{"year":2026,"claim":"Defined post-translational and competitive regulation of the protein itself: OGT-mediated O-GlcNAcylation at T277 stabilizes it in lipotoxic stress, and MYDGF competition at the STI1-4 domain blocks LCN2 degradation.","evidence":"Site-directed mutagenesis with PTM detection, LAMP1/lysosomal assays in MASH mice, and competitive domain-binding ferroptosis assays","pmids":["41795680","41942632"],"confidence":"Medium","gaps":["Generality of T277 O-GlcNAc regulation beyond lipotoxic context unknown","Single lab per finding"]},{"year":null,"claim":"How UBQLN1 selects between stabilizing and degrading a given STI-bound substrate, and how its phase-separation behavior integrates with proteasomal versus autophagic routing, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified rule distinguishing stabilized from degraded substrates","In vivo relevance of phase separation to substrate handling not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,12,19,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,9]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[12,21]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,9,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,16]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]}],"complexes":[],"partners":["EPS15","GABRA1","RPA1","TRIF","CD36","PGC1B","GPX4","PSMD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UMX0","full_name":"Ubiquilin-1","aliases":["Protein linking IAP with cytoskeleton 1","PLIC-1","hPLIC-1"],"length_aa":589,"mass_kda":62.5,"function":"Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and endoplasmic reticulum-associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome (PubMed:15147878). Plays a role in the ERAD pathway via its interaction with ER-localized proteins UBXN4, VCP and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:18307982, PubMed:19822669). Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy-related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:19148225, PubMed:20529957, PubMed:23459205). Negatively regulates the TICAM1/TRIF-dependent toll-like receptor signaling pathway by decreasing the abundance of TICAM1 via the autophagic pathway (PubMed:21695056). Promotes the ubiquitination and lysosomal degradation of ORAI1, consequently down-regulating the ORAI1-mediated Ca2+ mobilization (PubMed:23307288). Suppresses the maturation and proteasomal degradation of amyloid beta A4 protein (A4) by stimulating the lysine 63 (K63)-linked polyubiquitination. Delays the maturation of A4 by sequestering it in the Golgi apparatus and preventing its transport to the cell surface for subsequent processing (By similarity). Ubiquitinates BCL2L10 and thereby stabilizes protein abundance (PubMed:22233804) Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress (PubMed:18953672). Plays a key role in the regulation of the levels of PSEN1 by targeting its accumulation to aggresomes which may then be removed from cells by autophagocytosis (PubMed:21143716) Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress (PubMed:18953672). Plays a key role in the regulation of the levels of PSEN1 by targeting its accumulation to aggresomes which may then be removed from cells by autophagocytosis (PubMed:21143716)","subcellular_location":"Cytoplasm; Nucleus; Endoplasmic reticulum; Cytoplasmic vesicle, autophagosome; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UMX0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBQLN1","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL2","stoichiometry":10.0},{"gene":"DYNLL1","stoichiometry":4.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PSMC4","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBQLN1","total_profiled":1310},"omim":[{"mim_id":"609748","title":"UBIQUITIN-LIKE 7; UBL7","url":"https://www.omim.org/entry/609748"},{"mim_id":"605046","title":"UBIQUILIN 1; UBQLN1","url":"https://www.omim.org/entry/605046"},{"mim_id":"300264","title":"UBIQUILIN 2; UBQLN2","url":"https://www.omim.org/entry/300264"},{"mim_id":"211530","title":"BROWN-VIALETTO-VAN LAERE SYNDROME 1; BVVLS1","url":"https://www.omim.org/entry/211530"},{"mim_id":"105550","title":"FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 1; FTDALS1","url":"https://www.omim.org/entry/105550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBQLN1"},"hgnc":{"alias_symbol":["DSK2","PLIC-1","XDRP1","DA41"],"prev_symbol":[]},"alphafold":{"accession":"Q9UMX0","domains":[{"cath_id":"3.10.20.90","chopping":"37-107","consensus_level":"high","plddt":88.618,"start":37,"end":107},{"cath_id":"-","chopping":"184-292","consensus_level":"medium","plddt":68.0563,"start":184,"end":292},{"cath_id":"-","chopping":"388-477","consensus_level":"high","plddt":69.447,"start":388,"end":477},{"cath_id":"1.10.8.10","chopping":"540-589","consensus_level":"medium","plddt":82.1908,"start":540,"end":589}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMX0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMX0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMX0-F1-predicted_aligned_error_v6.png","plddt_mean":62.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBQLN1","jax_strain_url":"https://www.jax.org/strain/search?query=UBQLN1"},"sequence":{"accession":"Q9UMX0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UMX0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UMX0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMX0"}},"corpus_meta":[{"pmid":"15745979","id":"PMC_15745979","title":"Family-based association between Alzheimer's disease and variants in UBQLN1.","date":"2005","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15745979","citation_count":195,"is_preprint":false},{"pmid":"11528422","id":"PMC_11528422","title":"GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1.","date":"2001","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11528422","citation_count":192,"is_preprint":false},{"pmid":"25044403","id":"PMC_25044403","title":"MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1.","date":"2014","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25044403","citation_count":116,"is_preprint":false},{"pmid":"34001851","id":"PMC_34001851","title":"UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma.","date":"2021","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34001851","citation_count":107,"is_preprint":false},{"pmid":"17082820","id":"PMC_17082820","title":"The UBL domain of PLIC-1 regulates aggresome formation.","date":"2006","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/17082820","citation_count":79,"is_preprint":false},{"pmid":"10487753","id":"PMC_10487753","title":"Identification of XDRP1; 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it binds cyclin A1 and A2 (but not B-type cyclins) through its N-terminal UBL domain, requiring residues 130–160 of cyclin A1; bacterially expressed XDRP1 inhibits Ca2+-induced degradation of cyclin A but not cyclin B in frog egg extract; injection of XDRP1 into fertilized Xenopus eggs blocks embryonic cell division.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, cell-free degradation assay in frog egg extract, Xenopus microinjection\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of cyclin A degradation inhibition plus mutagenesis-level domain mapping plus in vivo injection phenotype, single study with multiple orthogonal methods\",\n      \"pmids\": [\"10487753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Two isoforms of Xenopus XDRP1 (XDRP1L and XDRP1S) differ in their UBL domain; both bind polyubiquitinated proteins via their UBA domains, but only XDRP1L binds the proteasome via its UBL domain, whereas XDRP1S (with a truncated UBL) fails to bind the proteasome and instead binds monomeric cyclin A and prevents its degradation.\",\n      \"method\": \"In vitro binding assays, pulldown with polyubiquitinated proteins, proteasome binding assays, cyclin A degradation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with domain-level analysis, single lab, single study\",\n      \"pmids\": [\"17027914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PLIC-1 (UBQLN1) inhibits Gβγ-dependent cell signaling (but not Gs-mediated adenylyl cyclase activation) by directly associating with Gβγ; this interaction does not require the UBL or UBA domains of PLIC-1; PLIC-1 co-localizes with G proteins in lamellae and pseudopods and inhibits SDF-1α-induced phospholipase C activation, CXCR4 internalization, and cell migration.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, confocal colocalization, chemotaxis assays, phospholipase C activation assay, adenylyl cyclase assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown and Co-IP with domain mapping, multiple functional readouts (PLC, migration, internalization), single lab\",\n      \"pmids\": [\"14662753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The UBL domain of PLIC-1 (UBQLN1) is required for aggresome formation; PLIC-1 binds UIM-containing proteins ataxin-3, HSJ1a, and EPS15 via its UBL domain; PLIC-1 and EPS15 localize to perinuclear aggresomes; polyQ expression enhances PLIC-1–EPS15 interaction; PLIC-1 knockdown reduces aggresome formation; a dominant-negative PLIC-1(ΔUBL) blocks polyQ transport to aggresomes and disrupts EPS15 association with aggregates; PLIC-1 is upregulated by arsenite-induced protein misfolding.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, dominant-negative overexpression, immunofluorescence/confocal microscopy, polyQ disease model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mutant, RNAi loss-of-function, dominant-negative, multiple binding partners identified, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17082820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PLIC-1 (UBQLN1) interacts with the TIR domain of TLR4 (via yeast two-hybrid) and with TRIF (confirmed by Co-IP and GST pulldown); PLIC-1 strongly suppresses TLR3-TRIF-dependent IFN-β promoter activation; PLIC-1 and TRIF co-localize with autophagosome marker LC3 in punctate structures; PLIC-1 overexpression decreases TRIF protein abundance in a nocodazole-sensitive manner; PLIC-1 knockdown by shRNA enhances TLR3 activation.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, GST pulldown, luciferase reporter assay, shRNA knockdown, confocal microscopy, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and GST pulldown plus loss-of-function with specific reporter readout, single lab\",\n      \"pmids\": [\"21695056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UBQLN1 interacts with SPEM1 (identified by yeast two-hybrid) and both proteins co-localize to the manchette of elongating spermatids, implicating UBQLN1 in regulation of protein ubiquitination during spermiogenesis.\",\n      \"method\": \"Yeast two-hybrid, immunofluorescence co-localization\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid and co-localization only, no functional mechanistic follow-up for UBQLN1 specifically\",\n      \"pmids\": [\"20558241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"DA41 (UBQLN1) interacts with the EGF-like protein S(1-5) through amino acids 155–232 of DA41, identified by yeast two-hybrid.\",\n      \"method\": \"Yeast two-hybrid, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only, no in-cell validation of interaction\",\n      \"pmids\": [\"9268694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The first two STI domains of UBQLN1 are critical for binding to the substrate BCLb (and similarly to IGF1R and ESYT2); interaction of UBQLN1 with BCLb is independent of BCLb ubiquitination, but interaction with ubiquitin via the UBA domain is required for substrate stabilization; UBL-mediated interactions (e.g., with PSMD4 and BAG6) do not result in substrate stabilization by UBQLN1. Thus, substrate fate (stabilization vs. degradation) is determined by the domain of UBQLN1 mediating substrate contact.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/mutation constructs, proteasome and ubiquitin-binding assays, Western blot\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level mapping with multiple substrates and orthogonal readouts (stabilization, ubiquitin binding), single lab\",\n      \"pmids\": [\"28075048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The missense mutation UBQLN1-E54D causes cytosolic aggregate formation and mislocalized TDP-43, and impairs degradation of ubiquitinated proteins through the proteasome in vitro, demonstrating that this mutation disrupts UPS function.\",\n      \"method\": \"In vitro functional studies, immunofluorescence, ubiquitinated protein degradation assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional UPS degradation assay plus aggregate/TDP-43 localization, single lab, single mutant\",\n      \"pmids\": [\"22766032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upregulated UBQLN1 in sorafenib-resistant HCC cells induces degradation of PGC1β in a ubiquitination-independent manner, attenuating mitochondrial biogenesis and ROS production.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, mitochondrial functional assays (oxygen consumption rate, mitochondrial DNA content), gain/loss-of-function experiments\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection with Co-IP, functional mitochondrial assays, and ubiquitination-independence demonstrated, single lab\",\n      \"pmids\": [\"34001851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD36 acts as a bridge molecule linking UBQLN1 to SNARE proteins (STX17, SNAP29, VAMP8) at the lysosome, promoting their proteasomal degradation in a UBQLN1-dependent manner, thereby impairing autophagosome-lysosome fusion.\",\n      \"method\": \"Co-immunoprecipitation, knockout and overexpression in mice and cells, autophagic flux assays, Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating ternary complex, KO rescue experiments, functional readout (autophagosome-lysosome fusion), single lab\",\n      \"pmids\": [\"37014234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The E6AP AZUL domain binds transiently to the UBA domain of UBQLN1/2; NOE spectroscopy identified direct intermolecular contacts; an AlphaFold2-Multimer model of the AZUL:UBA complex was generated; an oligomerization domain (UBAA) adjacent to the UBA is α-helical and is allosterically reconfigured by AZUL binding; E6AP interacts with UBQLN1/2 in cellulo and E6AP AZUL is recruited to UBQLN2 condensates in vitro.\",\n      \"method\": \"NMR (NOE spectroscopy, transfer NOE), AlphaFold2-Multimer structure prediction, in vitro condensate assay, co-immunoprecipitation in cells\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR with intermolecular NOE restraints plus structural modeling plus cellular Co-IP, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36827983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBQLN1 interacts with RPA1 and shuttles it off from the replication fork; UBQLN1 deficiency retains RPA1 at the replication fork, hinders replication, causes cell cycle arrest, genome instability, and rapid telomere shortening (particularly in telomere regions with G-rich sequences prone to replication stress).\",\n      \"method\": \"Co-immunoprecipitation, RPA1 ChIP at replication forks, UBQLN1 knockdown with telomere length measurement, cell cycle assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional knockdown with specific genomic readout (telomere shortening, replication fork assay), single lab\",\n      \"pmids\": [\"37463174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Full-length UBQLN1, UBQLN2, and UBQLN4 exhibit distinct phase separation behaviors in vitro; the short N-terminal disordered regions inhibit phase separation via electrostatic interactions; UBQLN1 does not phase separate with a temperature dependence (unlike UBQLN2, whose temperature-dependent behavior requires its unique proline-rich region absent in UBQLN1).\",\n      \"method\": \"In vitro phase separation assays with full-length proteins and charge variant/truncation constructs, biophysical characterization\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple deletion and charge variants, comparative analysis across family members, single lab\",\n      \"pmids\": [\"38041404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of DA41 (UBQLN1) in v-Ha-ras-transformed 3Y1 cells suppresses cell growth and reduces CDK2 kinase activity without altering CDK2 protein levels, indicating a role in cell cycle regulation.\",\n      \"method\": \"Stable transfection/overexpression, growth assays, soft agar colony formation, CDK2 kinase activity assay, Western blot\",\n      \"journal\": \"Japanese journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional overexpression with CDK2 activity assay readout, single lab, single study\",\n      \"pmids\": [\"11050468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Foxc1 functions as a transcriptional activator of Ubqln1; Sirt1 promotes Foxc1 expression by deacetylating Ezh2 and inhibiting its repressive activity on Foxc1; the Sirt1/Foxc1/Ubqln1 axis regulates proteostasis (ubiquitinated protein aggregation) and neuronal survival during cerebral ischemia/reperfusion injury.\",\n      \"method\": \"Co-IP, ChIP, dual-luciferase reporter assay, siRNA knockdown, MCAO/R and OGD/R models\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus dual-luciferase plus Co-IP for pathway placement, single lab\",\n      \"pmids\": [\"38452414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBQLN1 knockdown reduces p53 protein levels through activation of autophagy (not proteasomal degradation); inhibition of autophagy restores p53 levels in UBQLN1-KD cells; UBQLN1 KD inhibits mTOR and its downstream S6K phosphorylation.\",\n      \"method\": \"siRNA knockdown, autophagy inhibitor treatment, proteasome activity assay, MTT, BrdU, TUNEL assays, Western blot\",\n      \"journal\": \"Journal of thoracic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with pharmacological rescue and proteasome activity assay, single lab, single study\",\n      \"pmids\": [\"33209421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBQLN1 interacts with SNARE proteins and promotes their ubiquitin-mediated proteasomal degradation; its STI domain mediates binding to substrate GPX4 and stabilizes it (demonstrated in HCC); separately, UBQLN1 was shown to stabilize substrates through STI-domain interaction independent of substrate ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion experiments, Western blot, functional ferroptosis assays\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with domain implication, single study, limited mechanistic follow-up for UBQLN1 STI-GPX4 interaction specifically\",\n      \"pmids\": [\"41287824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBQLN1 mediates ubiquitin-dependent degradation of Pgm1; Sec13 competes with UBQLN1 for binding to Pgm1, thereby inhibiting UBQLN1-mediated Pgm1 ubiquitination and stabilizing Pgm1 to promote glycolysis.\",\n      \"method\": \"Co-immunoprecipitation demonstrating ternary complex (Sec13–Pgm1–Ubqln1), Ubqln1 overexpression/knockdown, Western blot for Pgm1 stability, ubiquitination assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with overexpression/KD, single lab, ubiquitination assay but abstract-level detail only\",\n      \"pmids\": [\"39159700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Lipotoxic stress induces O-GlcNAcylation at T277 of UBQLN1 by OGT, which competitively inhibits phosphorylation at the same site and reduces ubiquitin-mediated degradation of UBQLN1, stabilizing it; UBQLN1 in hepatocytes regulates MVB–lysosome fusion via LAMP1, promoting sEV secretion; sEV-carried UBQLN1 degrades the V-ATPase subunit ATP6V1B2 through E54D-dependent ubiquitin ligase activity, inhibiting lysosomal acidification and mitophagy in hepatic stellate cells.\",\n      \"method\": \"Co-IP, site-directed mutagenesis (T277), O-GlcNAc and phosphorylation detection, LAMP1 interaction assays, lysosomal acidification assay, hepatocyte-specific Ubqln1/Ogt knockdown in MASH mice\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM with mutagenesis plus functional downstream assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41795680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MYDGF competitively binds UBQLN1 at its STI1-4 domain, blocking UBQLN1-mediated ERAD recognition and degradation of LCN2, thereby stabilizing LCN2 and suppressing ferroptosis in gastric cancer under hypoxia.\",\n      \"method\": \"Co-immunoprecipitation, domain competition assay, LCN2 stability assay, ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with competitive domain binding plus functional ferroptosis readout, single lab\",\n      \"pmids\": [\"41942632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"UBQLN1 promotes ubiquitin-mediated degradation of SIKE, activating the p38 MAPK pathway to drive lipid accumulation in hepatocytes during MASH; genetic knockdown of UBQLN1 reduces SIKE degradation and suppresses p38 MAPK signaling, hepatic steatosis, and fibrosis.\",\n      \"method\": \"LC-MS/MS proteomics, transcriptomics, Co-IP, UBQLN1 knockdown in MASH mouse models and hepatocytes, Western blot\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and KD with pathway readout, abstract-level detail only, single lab\",\n      \"pmids\": [\"41814315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Disruption of PLIC-1 binding to GABA(A) receptors (by the PePα peptide) decreases miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal pyramidal neurons, while lentiviral overexpression of Plic-1 increases mIPSCs; these effects are blocked by the GABA(A)R inhibitor picrotoxin, confirming that Plic-1 regulates inhibitory synaptic transmission specifically through GABA(A) receptors.\",\n      \"method\": \"Intrahippocampal peptide injection, lentiviral overexpression, whole-cell patch-clamp electrophysiology (mIPSC recording) in rat and mouse models\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiological readout with pharmacological control (picrotoxin), in vivo and in vitro models, single lab\",\n      \"pmids\": [\"26415648\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBQLN1 (also known as PLIC-1, XDRP1, DA41) is a ubiquitin-like/ubiquitin-associated shuttle protein whose UBL domain engages the proteasome and UIM-containing proteins (including proteasomal subunit S5a/PSMD4, ataxin-3, EPS15, and the E3 ligase E6AP via its AZUL domain), whose STI chaperone-like domains bind and determine the fate of diverse substrates (BCLb, IGF1R, GPX4, LCN2, PGC1β, SNARE proteins, Pgm1), and whose UBA domain binds polyubiquitinated cargo; UBQLN1 stabilizes GABA(A) receptors in the ER and promotes their synaptic surface insertion, inhibits Gβγ-dependent G-protein signaling by direct association, facilitates aggresome formation via UBL–UIM interactions with EPS15, suppresses TLR3-TRIF innate immune signaling by reducing TRIF abundance, promotes proteasomal degradation of SNARE proteins (impairing autophagosome–lysosome fusion when upregulated), interacts with RPA1 to facilitate replication fork progression and telomere maintenance, undergoes O-GlcNAcylation at T277 (by OGT) that stabilizes it, and can modulate cell cycle progression (reducing CDK2 activity) and mitochondrial biogenesis (through ubiquitination-independent PGC1β degradation).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBQLN1 (PLIC-1, XDRP1, DA41) is a multidomain ubiquitin-like/ubiquitin-associated shuttle protein that controls the fate of diverse client proteins by coupling substrate recognition to the proteasome and to autophagy/lysosomal pathways [#5, #9]. Its N-terminal UBL domain engages UIM-containing partners including ataxin-3, HSJ1a, and EPS15 and is required for transport of polyQ aggregates to perinuclear aggresomes, while its UBA domain binds polyubiquitinated cargo [#5, #3]; the E6AP AZUL domain binds transiently to the UBA domain, allosterically reconfiguring an adjacent oligomerization element [#13]. Substrate destiny is set by which UBQLN1 domain contacts the client: STI-domain binding (to substrates such as BCLb, IGF1R, GPX4, and LCN2) plus UBA-mediated ubiquitin engagement stabilizes substrates, whereas UBL-mediated interactions route them toward turnover [#9, #22]. Through these activities UBQLN1 governs proteostasis and protein quality control: the disease-associated E54D mutation impairs proteasomal degradation of ubiquitinated proteins and causes cytosolic aggregation with TDP-43 mislocalization [#10], and a Sirt1/Foxc1 transcriptional axis upregulates UBQLN1 to protect neurons during ischemia/reperfusion [#17]. UBQLN1 also has substrate-specific regulatory roles in neurons, where it directly binds GABA(A) receptor subunits, stabilizes them in the ER, and increases their rate of surface insertion to enhance inhibitory synaptic transmission [#0, #1, #24]; in cell-cycle and growth control, where its UBL domain binds cyclin A and inhibits its degradation and its overexpression suppresses CDK2 activity [#2, #16]; and in G\\u03b2\\u03b3-dependent G-protein signaling, which it inhibits by direct, UBL/UBA-independent association with G\\u03b2\\u03b3 [#4]. More recent work places UBQLN1 in autophagy and metabolic disease, promoting proteasomal degradation of SNARE proteins (STX17, SNAP29, VAMP8) via a CD36 bridge to impair autophagosome\\u2013lysosome fusion [#12], degrading PGC1\\u03b2 in a ubiquitination-independent manner to limit mitochondrial biogenesis [#11], and being stabilized by OGT-dependent O-GlcNAcylation at T277 in a lipotoxic, MASH-relevant context [#21]. UBQLN1 additionally shuttles RPA1 off replication forks to support fork progression and telomere maintenance [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the first functional handle on the protein by identifying it as a cyclin A-binding factor whose UBL domain selectively blocks cyclin A degradation and arrests cell division.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro cyclin degradation in frog egg extract, and Xenopus microinjection\",\n      \"pmids\": [\"10487753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect cyclin A protection to a defined proteasome-targeting mechanism\", \"Human ortholog function not yet demonstrated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a neuronal substrate-stabilizing role, showing the protein binds GABA(A) receptor subunits and increases surface receptor availability without altering internalization.\",\n      \"evidence\": \"Co-IP, immunolocalization, and cell-surface/internalization assays in neurons\",\n      \"pmids\": [\"11528422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how binding promotes insertion not resolved at this stage\", \"Domain requirement on UBQLN1 not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed a ubiquitin-independent signaling function: direct association with G\\u03b2\\u03b3 inhibits chemokine-driven PLC activation, receptor internalization, and migration, separating signaling roles from the UBL/UBA domains.\",\n      \"evidence\": \"GST pulldown, Co-IP, chemotaxis and PLC assays\",\n      \"pmids\": [\"14662753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of G\\u03b2\\u03b3 binding unknown\", \"Physiological context of this inhibition not defined in vivo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected the protein to protein quality control by demonstrating its UBL domain recruits UIM proteins (ataxin-3, HSJ1a, EPS15) to drive polyQ aggresome formation.\",\n      \"evidence\": \"Co-IP, RNAi, dominant-negative \\u0394UBL, and confocal microscopy in a polyQ model\",\n      \"pmids\": [\"17082820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether aggresome targeting reflects degradation or sequestration not resolved\", \"Endogenous regulation of partner selection unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mechanistically refined the GABA(A) receptor role, showing ER stabilization and increased poly-ubiquitinated subunit abundance accelerate membrane insertion.\",\n      \"evidence\": \"Pulse-chase, biotinylation, and ubiquitination assays in recombinant and neuronal systems\",\n      \"pmids\": [\"18467327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ubiquitin ligase acting on receptor subunits not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended quality-control function to innate immunity, showing the protein suppresses TLR3-TRIF IFN-\\u03b2 signaling by lowering TRIF abundance.\",\n      \"evidence\": \"Y2H, Co-IP, GST pulldown, luciferase reporter, shRNA knockdown, and LC3 colocalization\",\n      \"pmids\": [\"21695056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIF loss is proteasomal or autophagic not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked the protein directly to neurodegenerative disease mechanism, showing the E54D mutation aggregates, mislocalizes TDP-43, and impairs proteasomal degradation of ubiquitinated substrates.\",\n      \"evidence\": \"In vitro UPS degradation assay and immunofluorescence of a single mutant\",\n      \"pmids\": [\"22766032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutant in vitro only\", \"Causality in a defined Mendelian disease not established here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the central logic of substrate fate, showing STI domains contact substrates (BCLb, IGF1R, ESYT2) and that UBA-ubiquitin binding stabilizes them while UBL interactions (PSMD4, BAG6) do not.\",\n      \"evidence\": \"Co-IP with domain deletion/mutation and ubiquitin/proteasome binding assays\",\n      \"pmids\": [\"28075048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why some STI-bound substrates are stabilized and others degraded not fully delineated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened roles into autophagy, replication, and structural understanding: a CD36 bridge targets SNARE proteins for degradation impairing autophagosome-lysosome fusion; the protein shuttles RPA1 off forks for telomere maintenance; and NMR/AF2 mapped E6AP AZUL binding to the UBA domain.\",\n      \"evidence\": \"Co-IP/KO autophagic flux assays; RPA1 ChIP and telomere length; NMR NOE and AlphaFold2-Multimer with cellular Co-IP\",\n      \"pmids\": [\"37014234\", \"37463174\", \"36827983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of E6AP-UBA binding for substrate handling unknown\", \"Whether CD36-SNARE and RPA1 roles intersect with canonical proteostasis unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed the protein in metabolic and disease networks, with substrate-specific control of GPX4, Pgm1, and SIKE, and an upstream Sirt1/Foxc1 transcriptional axis governing neuronal proteostasis.\",\n      \"evidence\": \"Co-IP, domain deletion, ubiquitination assays, ChIP/luciferase, and knockdown in disease models\",\n      \"pmids\": [\"38452414\", \"41287824\", \"39159700\", \"41814315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several substrate findings are abstract-level or single-study\", \"Whether degradation routes are proteasomal vs lysosomal varies by substrate\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined post-translational and competitive regulation of the protein itself: OGT-mediated O-GlcNAcylation at T277 stabilizes it in lipotoxic stress, and MYDGF competition at the STI1-4 domain blocks LCN2 degradation.\",\n      \"evidence\": \"Site-directed mutagenesis with PTM detection, LAMP1/lysosomal assays in MASH mice, and competitive domain-binding ferroptosis assays\",\n      \"pmids\": [\"41795680\", \"41942632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of T277 O-GlcNAc regulation beyond lipotoxic context unknown\", \"Single lab per finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBQLN1 selects between stabilizing and degrading a given STI-bound substrate, and how its phase-separation behavior integrates with proteasomal versus autophagic routing, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified rule distinguishing stabilized from degraded substrates\", \"In vivo relevance of phase separation to substrate handling not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 12, 19, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [12, 21]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 9, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 16]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EPS15\", \"GABRA1\", \"RPA1\", \"TRIF\", \"CD36\", \"PGC1B\", \"GPX4\", \"PSMD4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}