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TECPR1

Tectonin beta-propeller repeat-containing protein 1 · UniProt Q7Z6L1

Length
1165 aa
Mass
129.7 kDa
Annotated
2026-06-10
14 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TECPR1 is a membrane-targeting autophagy effector that couples lipid and protein recognition to ATG8/LC3 conjugation and autophagosome-lysosome handling (PMID:22342342, PMID:37409490). In canonical and selective autophagy it binds the ATG12-ATG5 conjugate in a complex that is mutually exclusive with ATG16L1, acquires PtdIns(3)P binding upon that association, and recruits ATG5 to autolysosomal membranes to drive autophagosome-lysosome fusion; its loss blocks degradation of LC3-II and p62 and causes accumulation of protein aggregates and depolarized mitochondria without affecting starvation-induced bulk autophagy (PMID:22342342, PMID:21575909). As a lysosome-resident tether it uses its WD-repeat domain to selectively bind LC3C on matured autophagosomes and its PH domain to bind PtdIns(4)P on lysosomes, delivering autophagosomes for aggrephagy (PMID:32532970). On damaged membranes TECPR1 acts as a sensor of cytosolically exposed sphingomyelin through its N-terminal DysF domain, with a solvent-exposed tryptophan (W154) required for binding and for subsequent LC3 conjugation; sphingomyelin recognition nucleates an ATG12-ATG5-TECPR1 E3-like complex that lipidates LC3 directly onto damaged lysosomal membranes independently of ATG16L1 and promotes lysosomal recovery (PMID:37381828, PMID:37409490). Beyond conjugation, TECPR1 binds PtdIns(4)P on damaged lysosomes and engages the kinesin KIF1A to drive membrane tubulation for lysosomal repair, a role with physiological consequence in a high-fat-diet liver injury model (PMID:41478856).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 High

    Established TECPR1 as a selective-autophagy factor by showing it is an ATG5-binding partner specifically required for clearing bacteria, aggregates, and damaged mitochondria but not bulk autophagy, defining a dedicated cargo-selective pathway.

    Evidence Co-IP, colocalization, Tecpr1 knockout MEFs, and intracellular Shigella assays, with WIPI-2 interaction defining a WIPI-2-Tecpr1-Atg5 axis

    PMID:21575909 PMID:21795850

    Open questions at the time
    • Molecular basis for cargo selectivity not defined
    • Did not resolve how TECPR1 distinguishes selective from canonical autophagy at the membrane level
  2. 2012 High

    Defined the biochemical logic of TECPR1 in fusion by showing it forms a mutually exclusive complex with ATG12-ATG5 versus ATG16, gains PtdIns(3)P binding only when conjugate-bound, and recruits ATG5 to autolysosomes to promote fusion.

    Evidence Reciprocal Co-IP, GST pulldown, lipid-binding assays, and GFP-mRFP-LC3 flux reporter with RNAi loss-of-function

    PMID:22342342

    Open questions at the time
    • Structural basis of the ATG12-ATG5/TECPR1 versus ATG16 switch not resolved
    • Did not address damaged-membrane or lipidation roles uncovered later
  3. 2020 High

    Resolved how TECPR1 is spatially targeted, showing the WD-repeat domain binds LC3C selectively while the PH domain binds PtdIns(4)P, jointly tethering autophagosomes to lysosomes for aggrephagy.

    Evidence Domain-specific binding assays, domain-swap (PH-to-tandem-FYVE) redirection, live-cell imaging, and LC3C knockdown in neural stem cells

    PMID:32532970

    Open questions at the time
    • Relationship between the PtdIns(3)P-dependent fusion role and PtdIns(4)P-dependent tethering role not reconciled
    • LC3C-specificity determinants in the WD domain not structurally mapped
  4. 2023 High

    Identified TECPR1 as a sphingomyelin sensor that nucleates an ATG16L1-independent E3-like complex, establishing a new mechanism for LC3 lipidation directly on damaged membranes.

    Evidence Crystal structure of the N'DysF domain with W154A mutagenesis, sphingomyelin-binding and LC3 lipidation assays, and ATG16L1/TECPR1 double-knockout epistasis with ESCRT and galectin pathways

    PMID:37381828 PMID:37409490

    Open questions at the time
    • How sphingomyelin exposure is decoded to assemble the E3-like complex in cells not fully defined
    • Quantitative contribution to lysosomal recovery versus ATG16L1 pathway unresolved
  5. 2024 Medium

    Consolidated the model that TECPR1-directed sphingomyelin targeting drives ATG16L1-independent LC3 lipidation at damaged lysosomes.

    Evidence Follow-up commentary integrating knockout, lipidation, and damage assays from the two parallel 2023 studies

    PMID:37872727

    Open questions at the time
    • No new independent experimental methods
    • Does not extend mechanism beyond prior reports
  6. 2025 Medium

    Extended the sphingomyelin-TECPR1 lipidation pathway to osmotic lysosomal damage, indicating LC3 is conjugated to rupture remnants rather than intact swollen lysosomes.

    Evidence ATG16L1-knockout cells under chloroquine-induced osmotic stress with immunofluorescence for TECPR1, galectin-3, LC3, V-ATPase, LAMP1, and PI4P

    PMID:40458442

    Open questions at the time
    • Single lab, imaging-based
    • Fate and function of LC3-positive rupture remnants not biochemically characterized
  7. 2026 High

    Revealed a conjugation-independent repair function: PtdIns(4)P-bound TECPR1 recruits KIF1A to tubulate damaged lysosomes for membrane component removal, with in vivo relevance to liver injury.

    Evidence In vitro GUV tubulation reconstitution, TECPR1-KIF1A Co-IP, knockout cells, LLOMe and glucose-starvation damage assays, and a high-fat-diet MAFLD mouse model

    PMID:41478856

    Open questions at the time
    • How tubulation-based repair coordinates with LC3 lipidation on the same damaged lysosome not defined
    • Stoichiometry and regulation of the TECPR1-KIF1A interaction unresolved
  8. 2026 Medium

    Provided the first full-length architecture, showing a hook-shaped molecule with cis-arranged DysF domains stabilized by a tectonin-PH bridge.

    Evidence Cryo-EM of full-length TECPR1 with molecular dynamics simulations (preprint)

    PMID:41889887

    Open questions at the time
    • Preprint without peer review and no mutagenesis validation of the proposed interfaces
    • Conformational changes upon ATG12-ATG5 or membrane engagement not captured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TECPR1's multiple membrane-recognition modes (PtdIns(3)P, PtdIns(4)P, LC3C, sphingomyelin) and its dual roles in LC3 lipidation versus KIF1A-driven tubulation are integrated and switched at a single damaged lysosome remains unresolved.
  • No unified structural model linking lipid/protein binding to conjugation versus repair output
  • Regulation determining which pathway TECPR1 executes is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005764 lysosome 3
Pathway
R-HSA-9612973 Autophagy 4
Partners
ATG12ATG5KIF1ALC3CWIPI2
Complex memberships
ATG12-ATG5-TECPR1 E3-like complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 TECPR1 binds the Atg12-Atg5 conjugate and phosphatidylinositol 3-phosphate (PtdIns[3]P) to promote autophagosome-lysosome fusion. TECPR1 and Atg16 form mutually exclusive complexes with the Atg12-Atg5 conjugate, and TECPR1 binds PtdIns(3)P only upon association with the Atg12-Atg5 conjugate. TECPR1 localizes to and recruits Atg5 to autolysosome membranes; its elimination leads to accumulation of autophagosomes and blocks autophagic degradation of LC3-II and p62. Co-immunoprecipitation, GST pulldown, live-cell imaging (GFP-mRFP-LC3), RNAi knockdown with LC3-II/p62 degradation assay, lipid-binding assay Molecular cell High 22342342
2011 Tecpr1 is an Atg5-binding partner that colocalizes with Atg5 at Shigella-containing phagophores and is required for efficient selective autophagy of bacteria, misfolded protein aggregates, and depolarized mitochondria, but has no effect on rapamycin- or starvation-induced canonical autophagy. Tecpr1 also interacts with WIPI-2 (yeast Atg18 homolog), and TECPR1-deficient MEFs show accumulation of protein aggregates and depolarized mitochondria. Co-immunoprecipitation, colocalization imaging, Tecpr1 knockout MEFs, intracellular Shigella multiplication assay, immunofluorescence Cell host & microbe High 21575909
2011 Tecpr1 interacts with the Atg12-Atg5-Atg16L1 complex via binding to Atg5, and WIPI-2-Tecpr1-Atg5 defines a selective autophagy pathway targeting bacteria, protein aggregates, and damaged mitochondria. Co-immunoprecipitation, immunofluorescence colocalization, pathway epistasis analysis in Tecpr1-deficient cells Autophagy Medium 21795850
2020 The N-terminal WD-repeat domain of TECPR1 selectively binds LC3C (not other LC3/ATG8 family members) on matured autophagosomes to recruit autophagosomes to lysosomes for aggrephagy. The PH domain of TECPR1 selectively binds PtdIns(4)P to target TECPR1 to PtdIns(4)P-containing lysosomes. Ectopic redirection of TECPR1 to endosomes (by replacing PH with tandem-FYVE) causes accumulation of LC3C autophagosomes at endosomes and prevents their delivery to lysosomes. Domain-specific binding assays, domain-swap experiments, live-cell imaging, knockdown of LC3C with aggrephagy readout in neural stem cells, lipid-binding assay (PtdIns[4]P) Nature communications High 32532970
2023 Upon lysosomal membrane damage, TECPR1 is recruited to damaged membranes via its N-terminal dysferlin domain upstream of galectin and lysophagy induction. At the damaged membrane, TECPR1 assembles an alternative ATG12-ATG5-TECPR1 E3-like complex that mediates ATG16L1-independent unconventional LC3 lipidation. ATG16L1/TECPR1 double knockout impairs lysosomal recovery following damage. Lysosomal damage assays (LLOMe), double-knockout (ATG16L1/TECPR1) cells, immunofluorescence, Western blot for LC3 lipidation, epistasis with ESCRT and galectin pathways EMBO reports High 37381828
2023 TECPR1 is a receptor for cytosolically exposed sphingomyelin, binding sphingomyelin through its N-terminal DysF domain (N'DysF). A crystal structure of N'DysF identified key residues required for the interaction, including a solvent-exposed tryptophan W154 essential for binding to sphingomyelin-positive membranes and for LC3 lipid conjugation. TECPR1 recruits ATG5 into an ATG5/ATG12-E3 ligase complex that mediates LC3 lipid conjugation independently of ATG16L1, analogous to a canonical E3 ligase with interchangeable receptor subunits. Crystal structure determination of N'DysF domain, site-directed mutagenesis (W154A), sphingomyelin-binding assay, LC3 lipidation assay in bacteria-invaded cells, ATG16L1-independent complex reconstitution The EMBO journal High 37409490
2024 The ATG12-ATG5-TECPR1 E3-like complex mediates LC3 lipidation at damaged lysosomal membranes via TECPR1-directed membrane targeting through direct sphingomyelin interaction, functioning independently of ATG16L1. Knockout cell lines, LC3 lipidation assay, lysosomal damage assays, co-immunoprecipitation (corroborating/commentary on PMID:37381828 and PMID:37409490) Autophagy Medium 37872727
2025 TECPR1 is recruited to swollen/osmotically damaged lysosomes that expose sphingomyelin (in ATG16L1-knockout cells), where the TECPR1:ATG5-ATG12 complex conjugates LC3 to lysosome remnants that have ruptured in response to osmotic imbalance (chloroquine treatment). LC3II was absent from swollen lysosomes but located to small puncta containing V-ATPase, LAMP1, galectin-3, and PI4P, suggesting LC3 conjugation to rupture remnants. ATG16L1-knockout cells, chloroquine-induced osmotic stress, immunofluorescence for TECPR1, galectin-3, LC3, V-ATPase, LAMP1, PI4P Autophagy reports Medium 40458442
2026 TECPR1 is recruited to damaged lysosomes via interaction with PI4P on damaged lysosomal membranes during glucose starvation or LLOMe-induced lysosomal membrane permeabilization. TECPR1 interacts with KIF1A to facilitate tubule formation from damaged lysosomes, enabling removal of damaged membrane components and lysosomal repair. In vitro reconstitution showed TECPR1 coordinates with KIF1A to drive tubulation from PI4P-enriched giant unilamellar vesicles (GUVs). TECPR1 deficiency exacerbates starvation-induced liver damage in a high-fat diet MAFLD mouse model. In vitro reconstitution of tubulation with GUVs, Co-immunoprecipitation (TECPR1-KIF1A), TECPR1 knockout cells and mouse model, lysosomal damage assays (LLOMe, glucose starvation), live-cell imaging Cell research High 41478856
2026 Full-length TECPR1 adopts an elongated hook-shaped architecture (cryo-EM structure) in which the two dysferlin domains are arranged in a cis configuration. An intramolecular interface between tectonin repeat 1 and PH domains forms a stabilizing bridge that contributes to the orientation of the DysF domains. Molecular dynamics simulations support maintenance of this structural arrangement during membrane association. Cryo-electron microscopy (full-length protein), molecular dynamics simulations bioRxivpreprint Medium 41889887
2025 In zebrafish macrophages infected with Streptococcus pneumoniae, knockdown of tecpr1a abolishes a pneumolysin-induced CASM pathway (distinct from LAP), consistent with sphingomyelin-Tecpr1-induced LC3 lipidation (STIL) functioning as a host defense mechanism against pore-forming toxin-mediated membrane disruption. Zebrafish larval infection model, tecpr1a morpholino knockdown, LC3 reporter imaging, genetic inhibition of autophagy genes bioRxivpreprint Low bio_10.1101_2025.02.11.637156

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Molecular cell 175 22342342
2011 A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens. Cell host & microbe 133 21575909
2023 An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes. EMBO reports 54 37381828
2023 TECPR1 conjugates LC3 to damaged endomembranes upon detection of sphingomyelin exposure. The EMBO journal 53 37409490
2020 TECPR1 promotes aggrephagy by direct recruitment of LC3C autophagosomes to lysosomes. Nature communications 46 32532970
2011 The role of Tecpr1 in selective autophagy as a cargo receptor. Autophagy 13 21795850
2024 ATG12-ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage. Autophagy 9 37872727
2022 TECPR1 Induces Apoptosis in Non-Small Cell Lung Carcinoma via ATG5 Upregulation-Induced Autophagy Promotion. Annals of clinical and laboratory science 5 36197771
2026 Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis. Cell research 4 41478856
2025 The TECPR1:ATG5-ATG12 complex conjugates LC3/ATG8 to damaged lysosomes that expose luminal glycans in response to osmotic imbalance. Autophagy reports 4 40458442
2023 TECPR1 helps bridge the CASM during lysosome damage. The EMBO journal 4 37638605
2023 The separate axes of TECPR1 and ATG16L1 in CASM. Autophagy 3 37676042
2024 Overexpression of TECPR1 improved cognitive function of P301S-tau mice via activation of autophagy in the early and late process. Aging cell 2 39511758
2026 Full length TECPR1 displays 'cis' Dysferlin domain architecture. bioRxiv : the preprint server for biology 0 41889887

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