{"gene":"TEX264","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2019,"finding":"TEX264 is an ER-resident single-pass transmembrane protein that acts as an ER-phagy receptor by binding LC3 and GABARAP family proteins via an LC3-interacting region (LIR) motif. A long intrinsically disordered region (IDR) is required for its ER-phagy receptor function to bridge the gap between the ER and autophagosomal membranes, independently of amino acid sequence. Deletion of TEX264 alone profoundly blocks ER-phagy, and combined deletion with FAM134B and CCPG1 almost completely abolishes it.","method":"Differential interactome screen (wild-type LC3B vs. LIR recognition-deficient mutant), immunoprecipitation, CRISPR/KO with ER-phagy flux assays, deletion mutagenesis of the IDR","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO with defined phenotype, domain mutagenesis, replicated by independent lab (PMID:31006537)","pmids":["31006538"],"is_preprint":false},{"year":2019,"finding":"TEX264 uses an LC3-interacting region (LIR) to traffic into ATG8-positive puncta that initiate from three-way ER tubule junctions and subsequently fuse with lysosomes during nutrient stress. LIR-dependent proximity biotinylation proteomics identified a cohort of autophagy regulatory proteins and cargo adaptors near TEX264. TEX264 knockout stabilizes a cohort of ER proteins during nutrient stress, establishing it as an ER-phagy receptor acting independently of other candidate receptors.","method":"Quantitative proteomics during nutrient stress, LIR-mutant interaction/proximity biotinylation proteomics (BioID), CRISPR KO with global proteomics and ER-phagy flux assays, live-cell imaging","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, proximity biotinylation, KO phenotype, imaging), independent replication by second lab (PMID:31006538)","pmids":["31006537"],"is_preprint":false},{"year":2020,"finding":"TEX264 forms a complex with the p97 ATPase and the SPRTN metalloprotease to mediate upstream proteolysis of TOP1-DNA adducts (TOP1 cleavage complexes, TOP1cc). TEX264 recognizes both unmodified and SUMO1-modified TOP1 and recruits p97 and SPRTN to initiate TOP1cc repair. TEX264 localizes to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication.","method":"Co-immunoprecipitation, complex reconstitution, subcellular fractionation/localization, DNA replication fork association assays, functional rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, direct localization with functional consequence, multiple orthogonal methods in a single focused study","pmids":["32152270"],"is_preprint":false},{"year":2022,"finding":"Casein kinase 2 phosphorylates two serine residues upstream of the core LIR motif of TEX264, and this phosphorylation is critical for TEX264 interaction with ATG8 proteins, autophagosomal localization, and ER-phagy. Structural analysis showed that phosphorylation of these serines increases binding affinity via multiple hydrogen bonds with ATG8s that cannot be mimicked by substitution with acidic residues (phosphomimetics). This mechanism is distinct from other ER-phagy receptors that use a downstream helix to increase affinity.","method":"Kinase identification (CK2), in vitro phosphorylation assay, structural analysis of phospho-LIR–ATG8 complex, mutagenesis (phospho-dead and phosphomimetic mutants), autophagosomal localization assay, ER-phagy flux assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural analysis with functional validation, in vitro kinase assay, mutagenesis, and cellular phenotype in a single rigorous study","pmids":["35417087"],"is_preprint":false},{"year":2024,"finding":"TEX264 acts as a TOP1cc sensor at DNA replication forks and mediates selective autophagic degradation of TOP1cc DNA lesions by directing their export from the nucleus to lysosomes through a transient alteration of the nuclear envelope. This process is dependent on MRE11 nuclease and ATR kinase activity and involves p97 ATPase-mediated TOP1cc processing. This lysosomal DNA repair pathway is independent of the proteasome and evolutionarily conserved.","method":"Live-cell imaging, genetic KO/KD (TEX264, MRE11, ATR), TOP1cc repair assays, lysosomal degradation assays, cell survival assays, DNA replication fork analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genetic and cell biological methods in a focused mechanistic study, published in high-impact peer-reviewed journal","pmids":["39265577"],"is_preprint":false},{"year":2022,"finding":"TEX264 interacts with sorting nexin 27 (SNX27) and promotes recycling of membrane proteins (including Itgα5) from endosomes to the cell plasma membrane by recruiting SNX27 retromer vesicles. siRNA-mediated knockdown of TEX264 in HeLa cells significantly inhibits cell migration through reduction of SNX27-mediated Itgα5 receptor membrane recycling.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, cell migration assay, interactome screen in rat brain","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP confirmation, knockdown phenotype, single lab, no domain-level mechanistic dissection","pmids":["35837377"],"is_preprint":false},{"year":2026,"finding":"TEX264 interacts with WIPI2 to induce ER-phagy, leading to degradation of STING and negative regulation of type I interferon (IFN-I) response following HSV-1 infection. Overexpression of TEX264 inhibits IFN-I signaling triggered by HSV-1 or poly(dA:dT) and enhances HSV-1 replication.","method":"Co-immunoprecipitation (TEX264-WIPI2), overexpression/knockdown, IFN-I signaling assays, STING protein level measurement, viral replication assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP, overexpression/KD phenotype, single lab, no mutagenesis or structural validation","pmids":["41910346"],"is_preprint":false},{"year":2026,"finding":"OTUD3 deubiquitylase stabilizes TEX264 protein, and this stabilization by OTUD3 is required for teniposide-induced ER-phagy and subsequent KDM5B degradation in lung cancer cells.","method":"Genetic knockdown (OTUD3, TEX264), deubiquitylase activity assay, ER-phagy flux assay, KDM5B protein level measurement","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — KD phenotype, deubiquitylase assay, single lab, mechanistic details limited in abstract","pmids":["41763483"],"is_preprint":false},{"year":2024,"finding":"A capture complex composed of NBR1 and TEX264 facilitates targeting of ER-retained MHC-I for autophagic degradation in pancreatic ductal adenocarcinoma (PDAC) cells. Suppression of either TEX264 or NBR1 is sufficient to increase total MHC-I levels and re-route it to the plasma membrane. Binding of MHC-I to the TEX264-NBR1 complex is linked to antigen presentation efficiency and is increased when antigen loading is inhibited.","method":"Co-immunoprecipitation (TEX264-NBR1-MHC-I), CRISPRi knockdown, flow cytometry/MHC-I surface levels, CRISPRi genome-wide screen","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and KD phenotype, preprint, single lab, no structural validation","pmids":["bio_10.1101_2024.10.27.620516"],"is_preprint":true},{"year":2024,"finding":"TEX264 (and RETREG1/FAM134B) is identified as a mediator of elevated ER-phagy in skeletal muscle during starvation, as determined by LC3B-positive autophagosome cargo profiling from GFP-LC3 transgenic mice.","method":"Autophagosome isolation from GFP-LC3 transgenic mice, quantitative proteomics (LC-MS/MS)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proteomics method, preprint, no direct mechanistic dissection of TEX264 function","pmids":["bio_10.1101_2024.09.29.615610"],"is_preprint":true},{"year":2024,"finding":"TEX264, as a transmembrane ER-phagy receptor, can initiate autophagosome biogenesis via two pathways: by recruiting the upstream FIP200/ULK1 complex and via a WIPI-ATG13 complex, demonstrating flexibility in the assembly of the autophagy initiation machinery.","method":"In vitro reconstitution of autophagy initiation, genetic epistasis (dominant-negative and KO approaches), interaction assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution is strong method but preprint and single study without independent replication","pmids":["bio_10.1101_2024.08.28.609967"],"is_preprint":true},{"year":2025,"finding":"In differentiating keratinocytes, ectopic TEX264 expression is sufficient to fragment the ER, and in highly differentiated keratinocytes accelerates ER elimination and induces nuclear shrinkage; these effects are abolished by mutating the LIR motif required for autophagic function. TEX264 knockout or inhibition of its activation disrupts maturation of organotypic epidermal cultures, establishing a critical role for reticulophagy in cornification.","method":"Live confocal imaging of stratified human organotypic epidermis, ectopic overexpression, LIR-mutant rescue, KO of TEX264, organotypic culture maturation assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization with functional consequence, mutagenesis, KO phenotype, but preprint and single lab","pmids":["40904818"],"is_preprint":true}],"current_model":"TEX264 is a single-pass ER-resident transmembrane protein with a GyrI-like domain and intrinsically disordered C-terminus that functions as a major ER-phagy receptor by engaging ATG8/LC3/GABARAP proteins via a LIR motif phosphorylated by casein kinase 2, bridging the ER to autophagosomes through its disordered region; it also localizes to the nuclear periphery/replication forks where it coordinates a p97-SPRTN complex to proteolyze TOP1-DNA adducts (TOP1cc) and mediates their selective autophagic delivery to lysosomes in an MRE11- and ATR-dependent manner, while additionally interacting with SNX27 to regulate membrane protein recycling and with WIPI2 to degrade STING via ER-phagy."},"narrative":{"mechanistic_narrative":"TEX264 is an ER-resident single-pass transmembrane protein that serves as a major selective autophagy (ER-phagy) receptor, coupling the endoplasmic reticulum to autophagosomes during nutrient stress [PMID:31006538, PMID:31006537]. It engages LC3 and GABARAP family ATG8 proteins through an LC3-interacting region (LIR) and uses a long intrinsically disordered region to physically bridge the gap between the ER membrane and the forming autophagosome, a tethering function that depends on the length rather than the sequence of the disordered region [PMID:31006538]. ATG8 engagement is gated by casein kinase 2 phosphorylation of two serines upstream of the core LIR, which raises ATG8-binding affinity through phospho-specific hydrogen bonds and is required for autophagosomal localization and ER-phagy flux [PMID:35417087]. Loss of TEX264 alone profoundly blocks ER-phagy and stabilizes a cohort of ER proteins, and its combined deletion with FAM134B and CCPG1 nearly abolishes the pathway, marking it as a dominant, non-redundant receptor [PMID:31006538, PMID:31006537]. Beyond bulk ER turnover, TEX264 acts as a cargo-selective adaptor: it cooperates with NBR1 to route ER-retained MHC-I for autophagic degradation [PMID:bio_10.1101_2024.10.27.620516] and interacts with WIPI2 to degrade STING and dampen the type I interferon response after HSV-1 infection [PMID:41910346]. In a distinct nuclear-peripheral role, TEX264 localizes to DNA replication forks where it senses TOP1-DNA cleavage complexes (TOP1cc) and assembles a p97-SPRTN proteolytic complex to initiate their repair [PMID:32152270], additionally directing TOP1cc lesions out of the nucleus for lysosomal, proteasome-independent degradation in an MRE11- and ATR-dependent manner [PMID:39265577]. Its protein levels are controlled by the deubiquitylase OTUD3 [PMID:41763483], and it additionally supports SNX27-dependent endosomal recycling of membrane proteins [PMID:35837377].","teleology":[{"year":2019,"claim":"Established that an ER turnover pathway requires a dedicated receptor by identifying TEX264 as an ATG8-binding ER-phagy receptor whose disordered region physically bridges ER to autophagosome.","evidence":"Differential LC3B interactome screen, reciprocal Co-IP, CRISPR KO with ER-phagy flux, and IDR deletion mutagenesis; independently corroborated by proximity-biotinylation proteomics and KO proteomics during nutrient stress","pmids":["31006538","31006537"],"confidence":"High","gaps":["How the IDR length is matched to autophagosome geometry was not defined","Regulation of receptor activation under different stresses not addressed"]},{"year":2020,"claim":"Revealed a second, nuclear-peripheral function: TEX264 nucleates a p97-SPRTN complex to proteolyze TOP1-DNA adducts at replication forks, linking it to genome maintenance.","evidence":"Co-IP, complex reconstitution, subcellular fractionation, and replication-fork association assays","pmids":["32152270"],"confidence":"High","gaps":["Structural basis of TOP1cc recognition not resolved","How TEX264 partitions between ER-phagy and nuclear roles unknown"]},{"year":2022,"claim":"Defined the switch controlling ER-phagy receptor activity: CK2 phosphorylation of LIR-adjacent serines increases ATG8 affinity through phospho-specific contacts, distinguishing TEX264 from other receptors.","evidence":"CK2 identification, in vitro kinase assay, structural analysis of the phospho-LIR–ATG8 complex, and phospho-dead/phosphomimetic mutagenesis with ER-phagy flux","pmids":["35417087"],"confidence":"High","gaps":["Upstream signals activating CK2 toward TEX264 not identified","Whether dephosphorylation terminates ER-phagy not addressed"]},{"year":2022,"claim":"Extended TEX264 function beyond autophagy to endosomal trafficking, showing it recruits SNX27 retromer to recycle membrane proteins and support cell migration.","evidence":"Co-IP, immunofluorescence co-localization, siRNA knockdown, and cell migration assay","pmids":["35837377"],"confidence":"Medium","gaps":["Single Co-IP without domain-level mechanistic dissection","Relationship to ER-resident topology of TEX264 unexplained"]},{"year":2024,"claim":"Demonstrated a non-canonical, autophagy-based DNA repair route in which TEX264 senses TOP1cc and exports the lesions from the nucleus to lysosomes, independent of the proteasome.","evidence":"Live-cell imaging, KO/KD of TEX264, MRE11 and ATR, TOP1cc and lysosomal degradation assays, and survival/fork analysis","pmids":["39265577"],"confidence":"High","gaps":["Molecular details of the transient nuclear envelope alteration not resolved","How autophagy machinery accesses nuclear cargo unclear"]},{"year":2024,"claim":"Showed TEX264 selects specific cargo for autophagy, partnering with NBR1 to degrade ER-retained MHC-I and thereby tune antigen presentation in PDAC cells.","evidence":"Co-IP of TEX264-NBR1-MHC-I, CRISPRi knockdown, surface MHC-I flow cytometry, and genome-wide CRISPRi screen (preprint)","pmids":["bio_10.1101_2024.10.27.620516"],"confidence":"Medium","gaps":["Preprint, single lab without structural validation","Determinants of MHC-I selection by the complex not defined"]},{"year":2024,"claim":"Indicated mechanistic flexibility in autophagy initiation, with TEX264 able to recruit either FIP200/ULK1 or a WIPI-ATG13 module to seed autophagosomes.","evidence":"In vitro reconstitution of autophagy initiation, genetic epistasis, and interaction assays (preprint)","pmids":["bio_10.1101_2024.08.28.609967"],"confidence":"Medium","gaps":["Preprint without independent replication","When each initiation route is used in cells not established"]},{"year":2026,"claim":"Connected TEX264-driven ER-phagy to innate immune control by showing it engages WIPI2 to degrade STING and suppress type I interferon, promoting HSV-1 replication.","evidence":"Co-IP (TEX264-WIPI2), overexpression/knockdown, IFN-I signaling and STING level assays, and viral replication assay","pmids":["41910346"],"confidence":"Medium","gaps":["Single Co-IP without mutagenesis or structural validation","Whether STING is a direct ER-phagy cargo not formally shown"]},{"year":2026,"claim":"Identified post-translational control of TEX264 abundance, with OTUD3 deubiquitylase stabilizing TEX264 to enable drug-induced ER-phagy and KDM5B degradation.","evidence":"Knockdown of OTUD3 and TEX264, deubiquitylase activity assay, ER-phagy flux, and KDM5B level measurement","pmids":["41763483"],"confidence":"Medium","gaps":["Direct ubiquitin sites on TEX264 not mapped","Mechanistic detail limited; single lab"]},{"year":null,"claim":"How TEX264 is partitioned and switched between its ER-phagy, nuclear TOP1cc repair, and endosomal recycling functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for spatial/regulatory control across its distinct roles","Structural basis of cargo selectivity (MHC-I, STING, TOP1cc) undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5]}],"complexes":["TEX264-p97-SPRTN complex","TEX264-NBR1 capture complex"],"partners":["LC3B","GABARAP","P97","SPRTN","SNX27","WIPI2","NBR1","OTUD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6I9","full_name":"Testis-expressed protein 264","aliases":["Putative secreted protein Zsig11"],"length_aa":313,"mass_kda":34.2,"function":"Major reticulophagy (also called ER-phagy) receptor that acts independently of other candidate reticulophagy receptors to remodel subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006537, PubMed:31006538). The ATG8-containing isolation membrane (IM) cradles a tubular segment of TEX264-positive ER near a three-way junction, allowing the formation of a synapse of 2 juxtaposed membranes with trans interaction between the TEX264 and ATG8 proteins (PubMed:31006537). Expansion of the IM would extend the capture of ER, possibly through a 'zipper-like' process involving continued trans TEX264-ATG8 interactions, until poorly understood mechanisms lead to the fission of relevant membranes and, ultimately, autophagosomal membrane closure (PubMed:31006537). Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: acts by bridging VCP/p97 to covalent DNA-protein cross-links (DPCs) and initiating resolution of DPCs by SPRTN (PubMed:32152270)","subcellular_location":"Endoplasmic reticulum membrane; Cytoplasmic vesicle, autophagosome; Cytoplasm, cytosol; Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9Y6I9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEX264","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TEX264","total_profiled":1310},"omim":[{"mim_id":"620608","title":"TESTIS-EXPRESSED GENE 264; TEX264","url":"https://www.omim.org/entry/620608"},{"mim_id":"616086","title":"SprT-LIKE N-TERMINAL DOMAIN PROTEIN; SPRTN","url":"https://www.omim.org/entry/616086"},{"mim_id":"601023","title":"VALOSIN-CONTAINING PROTEIN; VCP","url":"https://www.omim.org/entry/601023"},{"mim_id":"126420","title":"TOPOISOMERASE, DNA, I; TOP1","url":"https://www.omim.org/entry/126420"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TEX264"},"hgnc":{"alias_symbol":["ZSIG11","FLJ13935"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6I9","domains":[{"cath_id":"3.20.80.10","chopping":"44-197","consensus_level":"high","plddt":95.0336,"start":44,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6I9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6I9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6I9-F1-predicted_aligned_error_v6.png","plddt_mean":75.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEX264","jax_strain_url":"https://www.jax.org/strain/search?query=TEX264"},"sequence":{"accession":"Q9Y6I9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6I9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6I9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6I9"}},"corpus_meta":[{"pmid":"31006538","id":"PMC_31006538","title":"Intrinsically Disordered Protein TEX264 Mediates ER-phagy.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31006538","citation_count":301,"is_preprint":false},{"pmid":"31006537","id":"PMC_31006537","title":"TEX264 Is an Endoplasmic Reticulum-Resident ATG8-Interacting Protein Critical for ER Remodeling during Nutrient Stress.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31006537","citation_count":246,"is_preprint":false},{"pmid":"32152270","id":"PMC_32152270","title":"TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32152270","citation_count":89,"is_preprint":false},{"pmid":"39265577","id":"PMC_39265577","title":"TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival.","date":"2024","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/39265577","citation_count":38,"is_preprint":false},{"pmid":"35417087","id":"PMC_35417087","title":"Phosphorylation by casein kinase 2 enhances the interaction between ER-phagy receptor TEX264 and ATG8 proteins.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35417087","citation_count":38,"is_preprint":false},{"pmid":"31362563","id":"PMC_31362563","title":"TEX264 is a major receptor for mammalian reticulophagy.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31362563","citation_count":32,"is_preprint":false},{"pmid":"33726628","id":"PMC_33726628","title":"TEX264 at the intersection of autophagy and DNA repair.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33726628","citation_count":27,"is_preprint":false},{"pmid":"35061945","id":"PMC_35061945","title":"Anti-Inflammatory Anthranilate Analogue Enhances Autophagy through mTOR and Promotes ER-Turnover through TEX264 during Alzheimer-Associated Neuroinflammation.","date":"2022","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35061945","citation_count":17,"is_preprint":false},{"pmid":"36041015","id":"PMC_36041015","title":"When acidic residues do not mimic phosphorylation: high-affinity binding of the reticulophagy receptor TEX264 to LC3/GABARAP.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/36041015","citation_count":5,"is_preprint":false},{"pmid":"39550277","id":"PMC_39550277","title":"TEX264-mediated selective autophagy directs DNA damage repair.","date":"2024","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39550277","citation_count":1,"is_preprint":false},{"pmid":"35837377","id":"PMC_35837377","title":"Tex264 Binding to SNX27 Regulates Itgα5 Receptor Membrane Recycling and Affects Cell Migration.","date":"2022","source":"BioMed research 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machinery","date":"2024-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.28.609967","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11495,"output_tokens":3411,"usd":0.042825,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10860,"output_tokens":3563,"usd":0.071688,"stage2_stop_reason":"end_turn"},"total_usd":0.114513,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"TEX264 is an ER-resident single-pass transmembrane protein that acts as an ER-phagy receptor by binding LC3 and GABARAP family proteins via an LC3-interacting region (LIR) motif. A long intrinsically disordered region (IDR) is required for its ER-phagy receptor function to bridge the gap between the ER and autophagosomal membranes, independently of amino acid sequence. Deletion of TEX264 alone profoundly blocks ER-phagy, and combined deletion with FAM134B and CCPG1 almost completely abolishes it.\",\n      \"method\": \"Differential interactome screen (wild-type LC3B vs. LIR recognition-deficient mutant), immunoprecipitation, CRISPR/KO with ER-phagy flux assays, deletion mutagenesis of the IDR\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO with defined phenotype, domain mutagenesis, replicated by independent lab (PMID:31006537)\",\n      \"pmids\": [\"31006538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEX264 uses an LC3-interacting region (LIR) to traffic into ATG8-positive puncta that initiate from three-way ER tubule junctions and subsequently fuse with lysosomes during nutrient stress. LIR-dependent proximity biotinylation proteomics identified a cohort of autophagy regulatory proteins and cargo adaptors near TEX264. TEX264 knockout stabilizes a cohort of ER proteins during nutrient stress, establishing it as an ER-phagy receptor acting independently of other candidate receptors.\",\n      \"method\": \"Quantitative proteomics during nutrient stress, LIR-mutant interaction/proximity biotinylation proteomics (BioID), CRISPR KO with global proteomics and ER-phagy flux assays, live-cell imaging\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, proximity biotinylation, KO phenotype, imaging), independent replication by second lab (PMID:31006538)\",\n      \"pmids\": [\"31006537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TEX264 forms a complex with the p97 ATPase and the SPRTN metalloprotease to mediate upstream proteolysis of TOP1-DNA adducts (TOP1 cleavage complexes, TOP1cc). TEX264 recognizes both unmodified and SUMO1-modified TOP1 and recruits p97 and SPRTN to initiate TOP1cc repair. TEX264 localizes to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication.\",\n      \"method\": \"Co-immunoprecipitation, complex reconstitution, subcellular fractionation/localization, DNA replication fork association assays, functional rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, direct localization with functional consequence, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"32152270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Casein kinase 2 phosphorylates two serine residues upstream of the core LIR motif of TEX264, and this phosphorylation is critical for TEX264 interaction with ATG8 proteins, autophagosomal localization, and ER-phagy. Structural analysis showed that phosphorylation of these serines increases binding affinity via multiple hydrogen bonds with ATG8s that cannot be mimicked by substitution with acidic residues (phosphomimetics). This mechanism is distinct from other ER-phagy receptors that use a downstream helix to increase affinity.\",\n      \"method\": \"Kinase identification (CK2), in vitro phosphorylation assay, structural analysis of phospho-LIR–ATG8 complex, mutagenesis (phospho-dead and phosphomimetic mutants), autophagosomal localization assay, ER-phagy flux assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural analysis with functional validation, in vitro kinase assay, mutagenesis, and cellular phenotype in a single rigorous study\",\n      \"pmids\": [\"35417087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEX264 acts as a TOP1cc sensor at DNA replication forks and mediates selective autophagic degradation of TOP1cc DNA lesions by directing their export from the nucleus to lysosomes through a transient alteration of the nuclear envelope. This process is dependent on MRE11 nuclease and ATR kinase activity and involves p97 ATPase-mediated TOP1cc processing. This lysosomal DNA repair pathway is independent of the proteasome and evolutionarily conserved.\",\n      \"method\": \"Live-cell imaging, genetic KO/KD (TEX264, MRE11, ATR), TOP1cc repair assays, lysosomal degradation assays, cell survival assays, DNA replication fork analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genetic and cell biological methods in a focused mechanistic study, published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"39265577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEX264 interacts with sorting nexin 27 (SNX27) and promotes recycling of membrane proteins (including Itgα5) from endosomes to the cell plasma membrane by recruiting SNX27 retromer vesicles. siRNA-mediated knockdown of TEX264 in HeLa cells significantly inhibits cell migration through reduction of SNX27-mediated Itgα5 receptor membrane recycling.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, cell migration assay, interactome screen in rat brain\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP confirmation, knockdown phenotype, single lab, no domain-level mechanistic dissection\",\n      \"pmids\": [\"35837377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TEX264 interacts with WIPI2 to induce ER-phagy, leading to degradation of STING and negative regulation of type I interferon (IFN-I) response following HSV-1 infection. Overexpression of TEX264 inhibits IFN-I signaling triggered by HSV-1 or poly(dA:dT) and enhances HSV-1 replication.\",\n      \"method\": \"Co-immunoprecipitation (TEX264-WIPI2), overexpression/knockdown, IFN-I signaling assays, STING protein level measurement, viral replication assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, overexpression/KD phenotype, single lab, no mutagenesis or structural validation\",\n      \"pmids\": [\"41910346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OTUD3 deubiquitylase stabilizes TEX264 protein, and this stabilization by OTUD3 is required for teniposide-induced ER-phagy and subsequent KDM5B degradation in lung cancer cells.\",\n      \"method\": \"Genetic knockdown (OTUD3, TEX264), deubiquitylase activity assay, ER-phagy flux assay, KDM5B protein level measurement\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD phenotype, deubiquitylase assay, single lab, mechanistic details limited in abstract\",\n      \"pmids\": [\"41763483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A capture complex composed of NBR1 and TEX264 facilitates targeting of ER-retained MHC-I for autophagic degradation in pancreatic ductal adenocarcinoma (PDAC) cells. Suppression of either TEX264 or NBR1 is sufficient to increase total MHC-I levels and re-route it to the plasma membrane. Binding of MHC-I to the TEX264-NBR1 complex is linked to antigen presentation efficiency and is increased when antigen loading is inhibited.\",\n      \"method\": \"Co-immunoprecipitation (TEX264-NBR1-MHC-I), CRISPRi knockdown, flow cytometry/MHC-I surface levels, CRISPRi genome-wide screen\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and KD phenotype, preprint, single lab, no structural validation\",\n      \"pmids\": [\"bio_10.1101_2024.10.27.620516\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEX264 (and RETREG1/FAM134B) is identified as a mediator of elevated ER-phagy in skeletal muscle during starvation, as determined by LC3B-positive autophagosome cargo profiling from GFP-LC3 transgenic mice.\",\n      \"method\": \"Autophagosome isolation from GFP-LC3 transgenic mice, quantitative proteomics (LC-MS/MS)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomics method, preprint, no direct mechanistic dissection of TEX264 function\",\n      \"pmids\": [\"bio_10.1101_2024.09.29.615610\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEX264, as a transmembrane ER-phagy receptor, can initiate autophagosome biogenesis via two pathways: by recruiting the upstream FIP200/ULK1 complex and via a WIPI-ATG13 complex, demonstrating flexibility in the assembly of the autophagy initiation machinery.\",\n      \"method\": \"In vitro reconstitution of autophagy initiation, genetic epistasis (dominant-negative and KO approaches), interaction assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution is strong method but preprint and single study without independent replication\",\n      \"pmids\": [\"bio_10.1101_2024.08.28.609967\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In differentiating keratinocytes, ectopic TEX264 expression is sufficient to fragment the ER, and in highly differentiated keratinocytes accelerates ER elimination and induces nuclear shrinkage; these effects are abolished by mutating the LIR motif required for autophagic function. TEX264 knockout or inhibition of its activation disrupts maturation of organotypic epidermal cultures, establishing a critical role for reticulophagy in cornification.\",\n      \"method\": \"Live confocal imaging of stratified human organotypic epidermis, ectopic overexpression, LIR-mutant rescue, KO of TEX264, organotypic culture maturation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization with functional consequence, mutagenesis, KO phenotype, but preprint and single lab\",\n      \"pmids\": [\"40904818\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TEX264 is a single-pass ER-resident transmembrane protein with a GyrI-like domain and intrinsically disordered C-terminus that functions as a major ER-phagy receptor by engaging ATG8/LC3/GABARAP proteins via a LIR motif phosphorylated by casein kinase 2, bridging the ER to autophagosomes through its disordered region; it also localizes to the nuclear periphery/replication forks where it coordinates a p97-SPRTN complex to proteolyze TOP1-DNA adducts (TOP1cc) and mediates their selective autophagic delivery to lysosomes in an MRE11- and ATR-dependent manner, while additionally interacting with SNX27 to regulate membrane protein recycling and with WIPI2 to degrade STING via ER-phagy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEX264 is an ER-resident single-pass transmembrane protein that serves as a major selective autophagy (ER-phagy) receptor, coupling the endoplasmic reticulum to autophagosomes during nutrient stress [#0, #1]. It engages LC3 and GABARAP family ATG8 proteins through an LC3-interacting region (LIR) and uses a long intrinsically disordered region to physically bridge the gap between the ER membrane and the forming autophagosome, a tethering function that depends on the length rather than the sequence of the disordered region [#0]. ATG8 engagement is gated by casein kinase 2 phosphorylation of two serines upstream of the core LIR, which raises ATG8-binding affinity through phospho-specific hydrogen bonds and is required for autophagosomal localization and ER-phagy flux [#3]. Loss of TEX264 alone profoundly blocks ER-phagy and stabilizes a cohort of ER proteins, and its combined deletion with FAM134B and CCPG1 nearly abolishes the pathway, marking it as a dominant, non-redundant receptor [#0, #1]. Beyond bulk ER turnover, TEX264 acts as a cargo-selective adaptor: it cooperates with NBR1 to route ER-retained MHC-I for autophagic degradation [#8] and interacts with WIPI2 to degrade STING and dampen the type I interferon response after HSV-1 infection [#6]. In a distinct nuclear-peripheral role, TEX264 localizes to DNA replication forks where it senses TOP1-DNA cleavage complexes (TOP1cc) and assembles a p97-SPRTN proteolytic complex to initiate their repair [#2], additionally directing TOP1cc lesions out of the nucleus for lysosomal, proteasome-independent degradation in an MRE11- and ATR-dependent manner [#4]. Its protein levels are controlled by the deubiquitylase OTUD3 [#7], and it additionally supports SNX27-dependent endosomal recycling of membrane proteins [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that an ER turnover pathway requires a dedicated receptor by identifying TEX264 as an ATG8-binding ER-phagy receptor whose disordered region physically bridges ER to autophagosome.\",\n      \"evidence\": \"Differential LC3B interactome screen, reciprocal Co-IP, CRISPR KO with ER-phagy flux, and IDR deletion mutagenesis; independently corroborated by proximity-biotinylation proteomics and KO proteomics during nutrient stress\",\n      \"pmids\": [\"31006538\", \"31006537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the IDR length is matched to autophagosome geometry was not defined\",\n        \"Regulation of receptor activation under different stresses not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a second, nuclear-peripheral function: TEX264 nucleates a p97-SPRTN complex to proteolyze TOP1-DNA adducts at replication forks, linking it to genome maintenance.\",\n      \"evidence\": \"Co-IP, complex reconstitution, subcellular fractionation, and replication-fork association assays\",\n      \"pmids\": [\"32152270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of TOP1cc recognition not resolved\",\n        \"How TEX264 partitions between ER-phagy and nuclear roles unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the switch controlling ER-phagy receptor activity: CK2 phosphorylation of LIR-adjacent serines increases ATG8 affinity through phospho-specific contacts, distinguishing TEX264 from other receptors.\",\n      \"evidence\": \"CK2 identification, in vitro kinase assay, structural analysis of the phospho-LIR\\u2013ATG8 complex, and phospho-dead/phosphomimetic mutagenesis with ER-phagy flux\",\n      \"pmids\": [\"35417087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Upstream signals activating CK2 toward TEX264 not identified\",\n        \"Whether dephosphorylation terminates ER-phagy not addressed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended TEX264 function beyond autophagy to endosomal trafficking, showing it recruits SNX27 retromer to recycle membrane proteins and support cell migration.\",\n      \"evidence\": \"Co-IP, immunofluorescence co-localization, siRNA knockdown, and cell migration assay\",\n      \"pmids\": [\"35837377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without domain-level mechanistic dissection\",\n        \"Relationship to ER-resident topology of TEX264 unexplained\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a non-canonical, autophagy-based DNA repair route in which TEX264 senses TOP1cc and exports the lesions from the nucleus to lysosomes, independent of the proteasome.\",\n      \"evidence\": \"Live-cell imaging, KO/KD of TEX264, MRE11 and ATR, TOP1cc and lysosomal degradation assays, and survival/fork analysis\",\n      \"pmids\": [\"39265577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular details of the transient nuclear envelope alteration not resolved\",\n        \"How autophagy machinery accesses nuclear cargo unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed TEX264 selects specific cargo for autophagy, partnering with NBR1 to degrade ER-retained MHC-I and thereby tune antigen presentation in PDAC cells.\",\n      \"evidence\": \"Co-IP of TEX264-NBR1-MHC-I, CRISPRi knockdown, surface MHC-I flow cytometry, and genome-wide CRISPRi screen (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.27.620516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, single lab without structural validation\",\n        \"Determinants of MHC-I selection by the complex not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Indicated mechanistic flexibility in autophagy initiation, with TEX264 able to recruit either FIP200/ULK1 or a WIPI-ATG13 module to seed autophagosomes.\",\n      \"evidence\": \"In vitro reconstitution of autophagy initiation, genetic epistasis, and interaction assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.08.28.609967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint without independent replication\",\n        \"When each initiation route is used in cells not established\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected TEX264-driven ER-phagy to innate immune control by showing it engages WIPI2 to degrade STING and suppress type I interferon, promoting HSV-1 replication.\",\n      \"evidence\": \"Co-IP (TEX264-WIPI2), overexpression/knockdown, IFN-I signaling and STING level assays, and viral replication assay\",\n      \"pmids\": [\"41910346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without mutagenesis or structural validation\",\n        \"Whether STING is a direct ER-phagy cargo not formally shown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified post-translational control of TEX264 abundance, with OTUD3 deubiquitylase stabilizing TEX264 to enable drug-induced ER-phagy and KDM5B degradation.\",\n      \"evidence\": \"Knockdown of OTUD3 and TEX264, deubiquitylase activity assay, ER-phagy flux, and KDM5B level measurement\",\n      \"pmids\": [\"41763483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct ubiquitin sites on TEX264 not mapped\",\n        \"Mechanistic detail limited; single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEX264 is partitioned and switched between its ER-phagy, nuclear TOP1cc repair, and endosomal recycling functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying model for spatial/regulatory control across its distinct roles\",\n        \"Structural basis of cargo selectivity (MHC-I, STING, TOP1cc) undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"TEX264-p97-SPRTN complex\", \"TEX264-NBR1 capture complex\"],\n    \"partners\": [\"LC3B\", \"GABARAP\", \"p97\", \"SPRTN\", \"SNX27\", \"WIPI2\", \"NBR1\", \"OTUD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}