Affinage

TEX264

Testis-expressed protein 264 · UniProt Q9Y6I9

Length
313 aa
Mass
34.2 kDa
Annotated
2026-06-10
14 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2019 High

    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

    PMID:31006537 PMID:31006538

    Open questions at the time
    • How the IDR length is matched to autophagosome geometry was not defined
    • Regulation of receptor activation under different stresses not addressed
  2. 2020 High

    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

    PMID:32152270

    Open questions at the time
    • Structural basis of TOP1cc recognition not resolved
    • How TEX264 partitions between ER-phagy and nuclear roles unknown
  3. 2022 High

    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

    PMID:35417087

    Open questions at the time
    • Upstream signals activating CK2 toward TEX264 not identified
    • Whether dephosphorylation terminates ER-phagy not addressed
  4. 2022 Medium

    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

    PMID:35837377

    Open questions at the time
    • Single Co-IP without domain-level mechanistic dissection
    • Relationship to ER-resident topology of TEX264 unexplained
  5. 2024 High

    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

    PMID:39265577

    Open questions at the time
    • Molecular details of the transient nuclear envelope alteration not resolved
    • How autophagy machinery accesses nuclear cargo unclear
  6. 2024 Medium

    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)

    PMID:bio_10.1101_2024.10.27.620516

    Open questions at the time
    • Preprint, single lab without structural validation
    • Determinants of MHC-I selection by the complex not defined
  7. 2024 Medium

    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)

    PMID:bio_10.1101_2024.08.28.609967

    Open questions at the time
    • Preprint without independent replication
    • When each initiation route is used in cells not established
  8. 2026 Medium

    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

    PMID:41910346

    Open questions at the time
    • Single Co-IP without mutagenesis or structural validation
    • Whether STING is a direct ER-phagy cargo not formally shown
  9. 2026 Medium

    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

    PMID:41763483

    Open questions at the time
    • Direct ubiquitin sites on TEX264 not mapped
    • Mechanistic detail limited; single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TEX264 is partitioned and switched between its ER-phagy, nuclear TOP1cc repair, and endosomal recycling functions remains unresolved.
  • No unifying model for spatial/regulatory control across its distinct roles
  • Structural basis of cargo selectivity (MHC-I, STING, TOP1cc) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005635 nuclear envelope 2 GO:0005783 endoplasmic reticulum 2 GO:0005768 endosome 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-73894 DNA Repair 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
GABARAPLC3BNBR1OTUD3P97SNX27SPRTNWIPI2
Complex memberships
TEX264-NBR1 capture complexTEX264-p97-SPRTN complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 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. Differential interactome screen (wild-type LC3B vs. LIR recognition-deficient mutant), immunoprecipitation, CRISPR/KO with ER-phagy flux assays, deletion mutagenesis of the IDR Molecular cell High 31006538
2019 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. 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 Molecular cell High 31006537
2020 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. Co-immunoprecipitation, complex reconstitution, subcellular fractionation/localization, DNA replication fork association assays, functional rescue experiments Nature communications High 32152270
2022 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. 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 EMBO reports High 35417087
2024 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. Live-cell imaging, genetic KO/KD (TEX264, MRE11, ATR), TOP1cc repair assays, lysosomal degradation assays, cell survival assays, DNA replication fork analysis Cell High 39265577
2022 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. Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, cell migration assay, interactome screen in rat brain BioMed research international Medium 35837377
2026 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. Co-immunoprecipitation (TEX264-WIPI2), overexpression/knockdown, IFN-I signaling assays, STING protein level measurement, viral replication assay The FEBS journal Medium 41910346
2026 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. Genetic knockdown (OTUD3, TEX264), deubiquitylase activity assay, ER-phagy flux assay, KDM5B protein level measurement European journal of pharmacology Medium 41763483
2024 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. Co-immunoprecipitation (TEX264-NBR1-MHC-I), CRISPRi knockdown, flow cytometry/MHC-I surface levels, CRISPRi genome-wide screen bioRxivpreprint Medium bio_10.1101_2024.10.27.620516
2024 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. Autophagosome isolation from GFP-LC3 transgenic mice, quantitative proteomics (LC-MS/MS) bioRxivpreprint Low bio_10.1101_2024.09.29.615610
2024 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. In vitro reconstitution of autophagy initiation, genetic epistasis (dominant-negative and KO approaches), interaction assays bioRxivpreprint Medium bio_10.1101_2024.08.28.609967
2025 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. Live confocal imaging of stratified human organotypic epidermis, ectopic overexpression, LIR-mutant rescue, KO of TEX264, organotypic culture maturation assay bioRxivpreprint Medium 40904818

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Intrinsically Disordered Protein TEX264 Mediates ER-phagy. Molecular cell 301 31006538
2019 TEX264 Is an Endoplasmic Reticulum-Resident ATG8-Interacting Protein Critical for ER Remodeling during Nutrient Stress. Molecular cell 246 31006537
2020 TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nature communications 89 32152270
2024 TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival. Cell 38 39265577
2022 Phosphorylation by casein kinase 2 enhances the interaction between ER-phagy receptor TEX264 and ATG8 proteins. EMBO reports 38 35417087
2019 TEX264 is a major receptor for mammalian reticulophagy. Autophagy 32 31362563
2021 TEX264 at the intersection of autophagy and DNA repair. Autophagy 27 33726628
2022 Anti-Inflammatory Anthranilate Analogue Enhances Autophagy through mTOR and Promotes ER-Turnover through TEX264 during Alzheimer-Associated Neuroinflammation. ACS chemical neuroscience 17 35061945
2022 When acidic residues do not mimic phosphorylation: high-affinity binding of the reticulophagy receptor TEX264 to LC3/GABARAP. Autophagy 5 36041015
2024 TEX264-mediated selective autophagy directs DNA damage repair. Trends in biochemical sciences 1 39550277
2022 Tex264 Binding to SNX27 Regulates Itgα5 Receptor Membrane Recycling and Affects Cell Migration. BioMed research international 1 35837377
2026 OTUD3-mediated deubiquitination licenses TEX264 to orchestrate ER-phagy for KDM5B degradation in teniposide lung cancer therapy. European journal of pharmacology 0 41763483
2026 TEX264 suppresses antiviral immune response by promoting STING degradation through ER-phagy. The FEBS journal 0 41910346
2025 The endoplasmic reticulum autophagy receptor TEX264 drives epidermal differentiation and is dysregulated in Darier disease. bioRxiv : the preprint server for biology 0 40904818

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