{"gene":"SEC62","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1989,"finding":"Yeast SEC62 encodes a membrane protein required for post-translational translocation of secretory precursor proteins into the ER lumen; the defect is membrane-specific (not cytosolic), and the protein is predicted to have two transmembrane domains with cytoplasmic N- and C-terminal domains including a C-terminal basic amphipathic helix for protein–protein interactions.","method":"In vitro translocation assay with sec62 mutant membranes/cytosol fractionation; DNA sequence analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with fractionation, replicated in multiple substrates","pmids":["2687286"],"is_preprint":false},{"year":2000,"finding":"Mammalian Sec62 physically associates with Sec61 and Sec63 in a ribosome-free complex in the ER membrane, forming a mammalian counterpart of the yeast Sec61p–Sec62p–Sec63p post-translational translocation complex.","method":"Biochemical fractionation, co-immunoprecipitation, primary sequence homology analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP and fractionation identifying the complex; foundational paper with high citation count","pmids":["10799540"],"is_preprint":false},{"year":2010,"finding":"Human Sec62 interacts with Sec63 (conserved from yeast) and additionally has gained the ability to interact with the ribosomal tunnel exit, supporting cotranslational protein transport into the ER—a function not present in yeast Sec62.","method":"Co-immunoprecipitation of Sec62 with ribosomes; interaction assays between Sec62 and Sec63","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with ribosomes and Sec63; single lab but multiple interaction assays","pmids":["20071467"],"is_preprint":false},{"year":2012,"finding":"Silencing SEC62 in human cells specifically inhibits post-translational (but not co-translational) transport of signal-peptide-containing precursor proteins into the ER, demonstrating a substrate-specific role for Sec62 in mammalian post-translational translocation.","method":"siRNA knockdown in HeLa cells; in vitro translocation assay with semi-permeabilized cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — siRNA KD with specific in vitro translocation readout, multiple substrates tested","pmids":["22375059"],"is_preprint":false},{"year":2012,"finding":"Mammalian Sec62-dependent translocation occurs post-translationally via the Sec61 translocon, requires ATP, and is specifically required for efficient secretion of small proteins (≤100 amino acids) with N-terminal signal sequences, serving as a fail-safe for the SRP pathway.","method":"SRP pathway impairment combined with SEC62 RNAi; in vitro translocation assays categorizing substrates by size","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — RNAi combined with in vitro translocation assay across multiple substrate classes; orthogonal perturbation of two pathways","pmids":["22648169"],"is_preprint":false},{"year":2012,"finding":"Protein kinase CK2 phosphorylates human Sec63 at serine residues 574, 576, and 748, and this phosphorylation enhances Sec63 binding to Sec62, which is a prerequisite for a functional ER protein translocon.","method":"CK2 phosphorylation mapping with deletion mutants and peptide library; pull-down and co-immunoprecipitation assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical mapping of phosphorylation sites plus co-IP showing functional consequence on Sec62–Sec63 interaction","pmids":["23287549"],"is_preprint":false},{"year":2013,"finding":"Sec62 mediates membrane insertion and orientation of moderately hydrophobic signal anchor proteins in the ER; defects in Sec62 selectively reduce translocation of type II (N-in, C-out) membrane topology, indicating a role in regulating signal sequence orientation during early translocation.","method":"Yeast Sec62 mutant strains; systematic analysis of model proteins with varying hydrophobicity and topology","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mutant analysis with multiple model substrates; yeast ortholog study with functional validation","pmids":["23632075"],"is_preprint":false},{"year":2013,"finding":"Sec62 protein directly and Ca2+-sensitively interacts with the Sec61 complex (major ER Ca2+ leak channel), and a Ca2+-binding motif in Sec62 is essential for this function; SEC62 silencing leads to elevated cytosolic Ca2+ and increased ER Ca2+ leakage, and Sec62 is required for tumor cell migration.","method":"Biacore surface plasmon resonance interaction analysis; Ca2+ imaging; siRNA depletion with migration assays; Ca2+-binding motif mutagenesis","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — SPR interaction assay plus Ca2+ imaging plus loss-of-function with defined phenotype; single lab, multiple orthogonal methods","pmids":["24304694"],"is_preprint":false},{"year":2014,"finding":"The Sec62–Sec63 complex in yeast facilitates translocation of the C-terminus of membrane proteins; mutations in the N-terminal cytosolic domain of Sec62 impair its interaction with Sec63 and cause defects in membrane insertion and C-terminal translocation of both single- and multi-spanning membrane proteins.","method":"Yeast Sec62 N-terminal domain mutants; co-IP to assess Sec62–Sec63 interaction; systematic analysis of single and multi-spanning membrane proteins","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — mutant analysis combined with interaction assay and multiple substrate topology analysis","pmids":["25097231"],"is_preprint":false},{"year":2015,"finding":"The SRP receptor (SRα) switches the Sec61 translocase from Sec62-dependent to SRP-dependent translocation by physically displacing Sec62 from Sec61; the charged linker region of SRα (between longin and GTPase domains) mediates this displacement.","method":"Truncation variants of SRα; crosslinking; in vitro translocation assays; co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution-style crosslinking and translocation assays with domain truncations; mechanistic link between SRP receptor and Sec62 displacement","pmids":["26634806"],"is_preprint":false},{"year":2015,"finding":"Sec62 and Sec63 are stabilized within the Sec61 translocon when the nascent polypeptide encounters a delay in translocation initiation (e.g., by passenger domain folding); the engaged nascent chain controls translocon composition, with Sec62/63-containing complexes forming when translocation initiation is slow.","method":"Ribosome-nascent chain complex isolation; co-immunoprecipitation of translocon components at defined translocation stages using model substrate preprolactin","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical capture of defined cotranslational intermediates with multiple substrates and multiple translocon components; strong mechanistic correlation","pmids":["25801167"],"is_preprint":false},{"year":2016,"finding":"Sec62 acts as an ER-resident autophagy receptor (recovER-phagy receptor) during recovery from ER stress, selectively delivering excess ER components to the autolysosomal system; this function requires a conserved LC3-interacting region (LIR) in the C-terminal cytosolic domain of Sec62, which is dispensable for its protein translocation function.","method":"Live-cell imaging; loss-of-function studies; LIR motif mutagenesis; autophagy flux assays in ER stress recovery conditions","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — LIR mutagenesis separating two distinct functions plus multiple imaging and flux assays; high citation count, widely replicated concept","pmids":["27749824"],"is_preprint":false},{"year":2020,"finding":"Human Sec62/Sec63-dependent ER import substrates share signal peptides with longer but less hydrophobic h-regions and lower C-region polarity; a slowly-gating signal peptide combined with a downstream positively-charged amino acid cluster is decisive for Sec62/Sec63 requirement, which may involve Sec62/Sec63 supporting Sec61-channel opening via direct interaction with the N-terminal cytosolic peptide of Sec61α or via BiP recruitment to ER-lumenal loop 7.","method":"Unbiased proteomics (in-cell protein import assay); siRNA knockdown; signal peptide mutagenesis; identification of 22 novel substrates","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased proteomics substrate identification combined with mutagenesis and multiple mechanistic follow-up experiments","pmids":["32133789"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of Sec61-Sec62-Sec63 complexes from S. cerevisiae and T. lanuginosus show that Sec62 and Sec63 activate Sec61 for post-translational translocation in a stepwise/hierarchical manner: Sec63 first partially opens the Sec61 lateral gate through cytosolic and luminal domain interactions, then Sec62 opens the translocation pore by displacing the plug domain; Sec62 may also prevent lipid invasion through the open lateral gate.","method":"Cryo-electron microscopy structure determination; molecular dynamics simulations; mutagenesis of Sec61–Sec63 interface residues","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures with multiple complex variants plus MD simulations; mechanistic model of stepwise gating directly validated by mutagenesis","pmids":["33398175"],"is_preprint":false},{"year":2021,"finding":"ATG9A acetylation status in the ER lumen controls induction of reticulophagy, and this requires ATG9A to engage SEC62 (as well as FAM134B) on the cytosolic side of the ER membrane.","method":"ATG9A interactome analysis in two mouse models of AT-1 dysregulation; co-immunoprecipitation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 — interactome/co-IP in mouse models; identifies SEC62 as ATG9A partner in reticulophagy but functional follow-up is limited","pmids":["33870132"],"is_preprint":false},{"year":2021,"finding":"Sec62 promotes gastric cancer metastasis by binding to LC3II and activating autophagy via the PERK/ATF4 pathway, with concomitant FIP200/Beclin-1/Atg5 activation; autophagy blockage abolishes Sec62-driven cell migration and invasion.","method":"Co-immunoprecipitation of Sec62 with LC3II; Western blot for UPR/autophagy markers; transwell migration/invasion assays; xenograft models; autophagy inhibitor rescue experiments","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional rescue experiments linking Sec62–LC3II interaction to autophagy-dependent metastasis; single lab","pmids":["35165763"],"is_preprint":false},{"year":2021,"finding":"SEC62 binds DDX3X, and DDX3X is essential for TLOC1/SEC62-induced oncogenic transformation (anchorage-independent growth); this interaction was identified by proteomic studies.","method":"Proteomic interaction studies (pulldown/MS); loss-of-function genetic screen; gain-of-function transformation assays","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — proteomics-identified interaction validated by loss-of-function; mechanistic link to transformation established","pmids":["23764425"],"is_preprint":false},{"year":2021,"finding":"SEC62 binds β-catenin and inhibits its degradation by competitively disrupting the interaction between β-catenin and APC, thereby preventing assembly of the β-catenin destruction complex and activating Wnt/β-catenin signaling in colorectal cancer cells.","method":"GST pull-down; co-immunoprecipitation; Western blot for β-catenin destruction complex components; siRNA loss-of-function with phenotypic readouts","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — GST pulldown plus co-IP plus competitive disruption assay; single lab but multiple orthogonal biochemical methods","pmids":["33858476"],"is_preprint":false},{"year":2022,"finding":"SEC62 activates the MAPK/JNK signaling pathway, leading to ATF2-mediated transcriptional upregulation of the lncRNA UCA1, which promotes colorectal cancer metastasis; blocking or activating JNK suppresses or enhances Sec62-mediated metastasis.","method":"RNA sequencing; rescue experiments with JNK inhibitor/agonist; luciferase reporter assay; ChIP assay; transwell/wound healing assays","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway placement by epistasis (JNK inhibitor rescue) plus ChIP and reporter assay; single lab","pmids":["36200182"],"is_preprint":false},{"year":2022,"finding":"Molecular dynamics simulations starting from cryo-EM structures show that the presence of Sec62 alters the conformational dynamics of the Sec61 lateral gate, plug, and pore region; without Sec62, the luminal side of the lateral gate closes toward the apo state, while with Sec62 bound it adopts a wider (active) conformation.","method":"Molecular dynamics simulations based on cryo-EM structures of Sec61 with/without Sec62","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Low","confidence_rationale":"Tier 4 — computational MD simulation only, no experimental validation of conformational changes","pmids":["36116515"],"is_preprint":false},{"year":2025,"finding":"SEC62 directly interacts with TRPM4 and promotes TRPM4 ubiquitination and proteasomal degradation; the compound cinobufagin binds SEC62 and disrupts the SEC62–TRPM4 interaction, thereby stabilizing TRPM4 and inducing necrosis by sodium overload in bortezomib-resistant myeloma cells.","method":"LiP-MS, molecular docking, MST and CETSA target engagement assays; SPR for SEC62–TRPM4 interaction; immunoprecipitation for ubiquitination; SEC62 knockdown validation","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple target engagement methods (MST, CETSA, SPR) plus ubiquitination assay; single lab but orthogonal biochemical methods","pmids":["40839992"],"is_preprint":false},{"year":2025,"finding":"SEC62-dependent ER-phagy in vascular endothelial cells promotes monocyte–endothelial cell adhesion and atherosclerosis; apelin-13 upregulates SEC62 to induce ER-phagy, and vascular endothelial cell-specific SEC62 deletion reduces atherosclerotic plaques in APOE-/- mice. Mechanistically, UBL4A mediates ubiquitin-like modification of ALDH1L1 at lysine-812, promoting ALDH1L1 insertion into the ER membrane and SEC62-dependent ER-phagy.","method":"siRNA knockdown; cell-specific knockout in APOE-/- mice with high-fat diet; co-immunoprecipitation; ubiquitination assay with lysine mutant","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic KO with defined phenotype plus biochemical interaction/ubiquitination assays; single lab","pmids":["39930135"],"is_preprint":false},{"year":2026,"finding":"SEC62 at mitochondria-associated membranes (MAMs) interacts directly with ATAD3B and suppresses ATAD3B expression, causing defective mitophagy, increased mitochondrial ROS, and inflammation, thereby driving MASH progression; hepatocyte-specific SEC62 overexpression worsens and SEC62 knockout ameliorates MASH phenotypes.","method":"Co-immunoprecipitation (SEC62–ATAD3B interaction); hepatocyte-specific KO and overexpression mouse models; mitophagy and ROS assays","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus bidirectional in vivo genetic manipulation with defined mechanistic readouts; single lab","pmids":["42001994"],"is_preprint":false},{"year":2026,"finding":"SEC62-mediated ER-phagy is deficient in Alzheimer's disease neurons; AAV-driven overexpression of SEC62 in 5×FAD mouse brains reduces Aβ plaque deposition, neuroinflammation, and cognitive impairment, establishing SEC62 ER-phagy as a mechanism for ER quality control relevant to AD pathology.","method":"Intrathecal AAV injection in 5×FAD mice; behavioral assays; immunostaining for Aβ and neuroinflammation markers; iPSC-derived neurons from AD patients","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain-of-function in disease model with multiple phenotypic readouts; single lab","pmids":["42026868"],"is_preprint":false},{"year":2024,"finding":"The intrinsically disordered regions (IDRs) of SEC62 exposed at the cytoplasmic face of the ER membrane (not its transmembrane domains) drive ER fragmentation during ER-phagy; the transmembrane domains determine sub-compartmental distribution but are dispensable for fragmentation.","method":"Domain swap experiments; live-cell imaging of ER fragmentation; loss-of-function and gain-of-function constructs for IDR and transmembrane domains","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2-3 — preprint; mechanistic domain dissection with imaging but not yet peer-reviewed","pmids":["bio_10.1101_2024.06.18.599470"],"is_preprint":true}],"current_model":"SEC62 encodes a conserved ER membrane protein that (1) functions as a component of the Sec61–Sec62–Sec63 post-translational translocation channel, where cryo-EM structures show Sec62 opens the Sec61 pore by displacing its plug domain in a hierarchical manner with Sec63, and whose engagement with specific substrates is governed by signal peptide hydrophobicity and downstream charged residues; (2) serves as an ER-phagy (recovER-phagy) receptor through a C-terminal LIR motif that engages LC3 to selectively deliver excess ER to autolysosomes during stress recovery; (3) regulates cytosolic Ca2+ homeostasis via a Ca2+-sensitive direct interaction with the Sec61 channel; and (4) participates in oncogenic signaling including Wnt/β-catenin pathway activation (by binding and stabilizing β-catenin) and MAPK/JNK-driven metastasis promotion, while its expression level is controlled by METTL3-mediated m6A modification of its mRNA."},"narrative":{"teleology":[{"year":1989,"claim":"Identification of SEC62 as an ER membrane component required for post-translational protein translocation established its fundamental cellular role, resolving whether the translocation defect was membrane-intrinsic or cytosolic.","evidence":"In vitro translocation assay with sec62 mutant membranes/cytosol fractionation in yeast","pmids":["2687286"],"confidence":"High","gaps":["No structural information on SEC62","Mammalian ortholog not yet identified","Mechanism of SEC62 action at the translocon unknown"]},{"year":2000,"claim":"Demonstration that mammalian Sec62 physically associates with Sec61 and Sec63 in a ribosome-free complex established the conservation of the post-translational translocation machinery from yeast to mammals.","evidence":"Reciprocal co-immunoprecipitation and biochemical fractionation of mammalian ER membranes","pmids":["10799540"],"confidence":"High","gaps":["Substrate specificity of the mammalian complex unknown","Whether Sec62 has gained new functions in mammals unclear"]},{"year":2010,"claim":"Discovery that human Sec62 can interact with the ribosomal tunnel exit raised the possibility that mammalian Sec62 has acquired cotranslational roles beyond its conserved post-translational function.","evidence":"Co-immunoprecipitation of Sec62 with ribosomes in human cells","pmids":["20071467"],"confidence":"Medium","gaps":["Functional significance of ribosome interaction for cotranslational transport not demonstrated","No structural detail of this interface"]},{"year":2012,"claim":"Systematic substrate analysis established that Sec62 is specifically required for post-translational (not cotranslational) ER import in mammalian cells, particularly for small secretory proteins with N-terminal signal sequences, revealing SEC62 as a fail-safe for the SRP pathway.","evidence":"siRNA knockdown in HeLa cells with in vitro translocation assays across multiple substrate classes; SRP pathway impairment combined with SEC62 RNAi","pmids":["22375059","22648169"],"confidence":"High","gaps":["Full client proteome not defined","Signal peptide features dictating Sec62 dependence not characterized"]},{"year":2012,"claim":"CK2 phosphorylation of Sec63 was shown to enhance its binding to Sec62, revealing a regulatory input that controls assembly of the functional translocon.","evidence":"Phosphorylation mapping with CK2 and co-immunoprecipitation of Sec62–Sec63","pmids":["23287549"],"confidence":"Medium","gaps":["In vivo relevance of CK2-mediated regulation not tested","Whether phosphorylation affects translocation efficiency directly unknown"]},{"year":2013,"claim":"Two discoveries expanded SEC62's roles: Sec62 was found to regulate signal anchor protein orientation during membrane insertion, and to regulate ER Ca²⁺ leak through a Ca²⁺-sensitive direct interaction with Sec61.","evidence":"Yeast Sec62 mutant analysis with model membrane proteins of varying topology; SPR interaction analysis and Ca²⁺ imaging with SEC62 siRNA depletion in human cells","pmids":["23632075","24304694"],"confidence":"Medium","gaps":["Structural basis of Ca²⁺-sensitive Sec62–Sec61 interaction unknown","Whether Ca²⁺ regulation and translocation functions are separable unclear"]},{"year":2015,"claim":"The SRP receptor was shown to physically displace Sec62 from Sec61, establishing the molecular switch mechanism between post-translational and cotranslational translocation modes, and Sec62/63 were found to be recruited when translocation initiation is delayed.","evidence":"Crosslinking and translocation assays with SRα truncation variants; ribosome-nascent chain complex isolation with co-IP of translocon components","pmids":["26634806","25801167"],"confidence":"High","gaps":["Structural basis of SRα-mediated Sec62 displacement not resolved","How translocation kinetics regulate Sec62/63 recruitment mechanistically unclear"]},{"year":2016,"claim":"The discovery that Sec62 functions as a selective ER-phagy receptor (recovER-phagy) through its C-terminal LIR motif — independent of its translocation role — revealed a second major function for this protein in ER homeostasis.","evidence":"LIR motif mutagenesis separating translocation and autophagy functions; autophagy flux assays during ER stress recovery","pmids":["27749824"],"confidence":"High","gaps":["Cargo selectivity mechanism for ER-phagy not defined","How SEC62-mediated ER-phagy is initiated and terminated unclear"]},{"year":2020,"claim":"Unbiased proteomics identified the signal peptide code for Sec62/Sec63 dependence — longer, less hydrophobic h-regions plus downstream positively charged residues — defining the substrate selection rules for this translocation pathway.","evidence":"In-cell protein import assay with siRNA knockdown; signal peptide mutagenesis across 22 novel substrates","pmids":["32789789"],"confidence":"High","gaps":["How signal peptide features mechanistically engage Sec62/Sec63 to open Sec61 not resolved at atomic level"]},{"year":2021,"claim":"Cryo-EM structures of the Sec61–Sec62–Sec63 complex revealed the stepwise gating mechanism: Sec63 first partially opens the Sec61 lateral gate, then Sec62 displaces the plug domain to open the pore, resolving the long-standing question of how post-translational translocation is activated.","evidence":"Cryo-EM structures from S. cerevisiae and T. lanuginosus with mutagenesis validation and MD simulations","pmids":["33398175"],"confidence":"High","gaps":["Structure of a substrate-engaged complex not available","Lipid-blocking role of Sec62 at the lateral gate not experimentally validated"]},{"year":2021,"claim":"Multiple studies established SEC62 as an oncogenic factor acting through diverse signaling pathways: binding and stabilizing β-catenin to activate Wnt signaling, activating MAPK/JNK to drive metastasis, and interacting with DDX3X to promote cellular transformation.","evidence":"GST pulldown and co-IP for β-catenin interaction; JNK inhibitor rescue and ChIP assays; proteomic identification of DDX3X interaction with transformation assays","pmids":["33858476","36200182","23764425"],"confidence":"Medium","gaps":["How an ER membrane protein accesses cytoplasmic/nuclear β-catenin mechanistically unresolved","Whether oncogenic functions depend on translocation or ER-phagy activities unknown","Single-lab findings for each pathway"]},{"year":2025,"claim":"SEC62-mediated ER-phagy was shown to have broad pathophysiological relevance: promoting atherosclerosis in endothelial cells, being deficient in Alzheimer's disease neurons (where its restoration reduces Aβ pathology), and interacting with ATAD3B at MAMs to suppress mitophagy and drive MASH.","evidence":"Endothelial-specific SEC62 KO in APOE−/− mice; AAV-SEC62 overexpression in 5×FAD mice; hepatocyte-specific SEC62 KO and overexpression with mitophagy assays","pmids":["39930135","42026868","42001994"],"confidence":"Medium","gaps":["Whether MAM localization represents a distinct pool from ER-phagy receptor pool unclear","Upstream signals controlling SEC62 expression in disease contexts incompletely mapped","Single-lab studies for each disease model"]},{"year":2025,"claim":"SEC62 was found to promote TRPM4 ubiquitination and proteasomal degradation through direct interaction, linking SEC62 to ion channel proteostasis and drug resistance in myeloma.","evidence":"SPR, MST, and CETSA target engagement assays; ubiquitination immunoprecipitation; SEC62 knockdown","pmids":["40839992"],"confidence":"Medium","gaps":["E3 ligase mediating TRPM4 ubiquitination through SEC62 not identified","Whether this represents a general SEC62 function in membrane protein quality control unknown"]},{"year":null,"claim":"Key unresolved questions include: the structure of a substrate-engaged Sec61–Sec62–Sec63 complex, how SEC62 transitions between its translocation and ER-phagy receptor functions, the mechanism by which an ER membrane protein activates cytoplasmic signaling pathways (Wnt, MAPK/JNK), and the structural basis by which SEC62's intrinsically disordered regions drive ER membrane fragmentation during ER-phagy.","evidence":"","pmids":[],"confidence":"Low","gaps":["No substrate-engaged cryo-EM structure","Functional switching mechanism between translocation and ER-phagy roles uncharacterized","Structural basis of ER fragmentation by SEC62 IDRs not peer-review validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,9,13]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[11,15,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,17,20]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,3,11,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,3,4,12,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,14,15,21,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,12]}],"complexes":["Sec61-Sec62-Sec63 translocon"],"partners":["SEC61A1","SEC63","LC3","CTNNB1","DDX3X","TRPM4","ATAD3B","ATG9A"],"other_free_text":[]},"mechanistic_narrative":"SEC62 is a conserved ER membrane protein that functions as a core component of the Sec61–Sec62–Sec63 post-translational translocation channel and as an ER-phagy receptor, linking ER protein import to ER quality control. In the translocation channel, Sec62 opens the Sec61 pore by displacing its plug domain in a hierarchical mechanism with Sec63, and is specifically required for post-translational import of substrates with less hydrophobic signal peptides, including small secretory proteins; the SRP receptor switches the translocon from Sec62-dependent to SRP-dependent mode by physically displacing Sec62 from Sec61 [PMID:33398175, PMID:22375059, PMID:26634806]. Independent of its translocation role, Sec62 acts as a selective ER-phagy (recovER-phagy) receptor during ER stress recovery through a C-terminal LC3-interacting region that recruits autophagic machinery, a function with physiological consequences in atherosclerosis, neurodegeneration, and liver disease [PMID:27749824, PMID:39930135, PMID:42026868]. SEC62 additionally regulates ER Ca²⁺ leak through Ca²⁺-sensitive interaction with Sec61 and promotes oncogenic signaling by stabilizing β-catenin against destruction-complex-mediated degradation and by activating the MAPK/JNK pathway [PMID:24304694, PMID:33858476, PMID:36200182]."},"prefetch_data":{"uniprot":{"accession":"Q99442","full_name":"Translocation protein SEC62","aliases":["Translocation protein 1","TP-1","hTP-1"],"length_aa":399,"mass_kda":45.9,"function":"Mediates post-translational transport of precursor polypeptides across endoplasmic reticulum (ER). Proposed to act as a targeting receptor for small presecretory proteins containing short and apolar signal peptides. Targets and properly positions newly synthesized presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q99442/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC62","classification":"Not Classified","n_dependent_lines":436,"n_total_lines":1208,"dependency_fraction":0.3609271523178808},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEC61B","stoichiometry":10.0},{"gene":"ANKRD46","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEC62","total_profiled":1310},"omim":[{"mim_id":"618271","title":"SEC61 TRANSLOCON, ALPHA-2 SUBUNIT; SEC61A2","url":"https://www.omim.org/entry/618271"},{"mim_id":"609214","title":"SEC61 TRANSLOCON, BETA SUBUNIT; SEC61B","url":"https://www.omim.org/entry/609214"},{"mim_id":"609213","title":"SEC61 TRANSLOCON, ALPHA-1 SUBUNIT; SEC61A1","url":"https://www.omim.org/entry/609213"},{"mim_id":"608648","title":"SEC63 HOMOLOG, PROTEIN TRANSLOCATION REGULATOR; SEC63","url":"https://www.omim.org/entry/608648"},{"mim_id":"602173","title":"SEC62 HOMOLOG, PREPROTEIN TRANSLOCATION FACTOR; SEC62","url":"https://www.omim.org/entry/602173"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Intermediate filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC62"},"hgnc":{"alias_symbol":["Dtrp1","HTP1"],"prev_symbol":["TLOC1"]},"alphafold":{"accession":"Q99442","domains":[{"cath_id":"-","chopping":"1-102_166-191","consensus_level":"medium","plddt":83.0895,"start":1,"end":191},{"cath_id":"1.10.287","chopping":"219-285","consensus_level":"high","plddt":80.5343,"start":219,"end":285}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99442","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99442-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99442-F1-predicted_aligned_error_v6.png","plddt_mean":65.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC62","jax_strain_url":"https://www.jax.org/strain/search?query=SEC62"},"sequence":{"accession":"Q99442","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99442.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99442/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99442"}},"corpus_meta":[{"pmid":"27749824","id":"PMC_27749824","title":"Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery.","date":"2016","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27749824","citation_count":374,"is_preprint":false},{"pmid":"10799540","id":"PMC_10799540","title":"Mammalian Sec61 is associated with Sec62 and Sec63.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10799540","citation_count":158,"is_preprint":false},{"pmid":"33858476","id":"PMC_33858476","title":"Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33858476","citation_count":156,"is_preprint":false},{"pmid":"2687286","id":"PMC_2687286","title":"SEC62 encodes a putative membrane protein required for protein translocation into the yeast endoplasmic reticulum.","date":"1989","source":"The Journal 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the defect is membrane-specific (not cytosolic), and the protein is predicted to have two transmembrane domains with cytoplasmic N- and C-terminal domains including a C-terminal basic amphipathic helix for protein–protein interactions.\",\n      \"method\": \"In vitro translocation assay with sec62 mutant membranes/cytosol fractionation; DNA sequence analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with fractionation, replicated in multiple substrates\",\n      \"pmids\": [\"2687286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mammalian Sec62 physically associates with Sec61 and Sec63 in a ribosome-free complex in the ER membrane, forming a mammalian counterpart of the yeast Sec61p–Sec62p–Sec63p post-translational translocation complex.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, primary sequence homology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and fractionation identifying the complex; foundational paper with high citation count\",\n      \"pmids\": [\"10799540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human Sec62 interacts with Sec63 (conserved from yeast) and additionally has gained the ability to interact with the ribosomal tunnel exit, supporting cotranslational protein transport into the ER—a function not present in yeast Sec62.\",\n      \"method\": \"Co-immunoprecipitation of Sec62 with ribosomes; interaction assays between Sec62 and Sec63\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with ribosomes and Sec63; single lab but multiple interaction assays\",\n      \"pmids\": [\"20071467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Silencing SEC62 in human cells specifically inhibits post-translational (but not co-translational) transport of signal-peptide-containing precursor proteins into the ER, demonstrating a substrate-specific role for Sec62 in mammalian post-translational translocation.\",\n      \"method\": \"siRNA knockdown in HeLa cells; in vitro translocation assay with semi-permeabilized cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — siRNA KD with specific in vitro translocation readout, multiple substrates tested\",\n      \"pmids\": [\"22375059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mammalian Sec62-dependent translocation occurs post-translationally via the Sec61 translocon, requires ATP, and is specifically required for efficient secretion of small proteins (≤100 amino acids) with N-terminal signal sequences, serving as a fail-safe for the SRP pathway.\",\n      \"method\": \"SRP pathway impairment combined with SEC62 RNAi; in vitro translocation assays categorizing substrates by size\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — RNAi combined with in vitro translocation assay across multiple substrate classes; orthogonal perturbation of two pathways\",\n      \"pmids\": [\"22648169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Protein kinase CK2 phosphorylates human Sec63 at serine residues 574, 576, and 748, and this phosphorylation enhances Sec63 binding to Sec62, which is a prerequisite for a functional ER protein translocon.\",\n      \"method\": \"CK2 phosphorylation mapping with deletion mutants and peptide library; pull-down and co-immunoprecipitation assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical mapping of phosphorylation sites plus co-IP showing functional consequence on Sec62–Sec63 interaction\",\n      \"pmids\": [\"23287549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sec62 mediates membrane insertion and orientation of moderately hydrophobic signal anchor proteins in the ER; defects in Sec62 selectively reduce translocation of type II (N-in, C-out) membrane topology, indicating a role in regulating signal sequence orientation during early translocation.\",\n      \"method\": \"Yeast Sec62 mutant strains; systematic analysis of model proteins with varying hydrophobicity and topology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant analysis with multiple model substrates; yeast ortholog study with functional validation\",\n      \"pmids\": [\"23632075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sec62 protein directly and Ca2+-sensitively interacts with the Sec61 complex (major ER Ca2+ leak channel), and a Ca2+-binding motif in Sec62 is essential for this function; SEC62 silencing leads to elevated cytosolic Ca2+ and increased ER Ca2+ leakage, and Sec62 is required for tumor cell migration.\",\n      \"method\": \"Biacore surface plasmon resonance interaction analysis; Ca2+ imaging; siRNA depletion with migration assays; Ca2+-binding motif mutagenesis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — SPR interaction assay plus Ca2+ imaging plus loss-of-function with defined phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24304694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Sec62–Sec63 complex in yeast facilitates translocation of the C-terminus of membrane proteins; mutations in the N-terminal cytosolic domain of Sec62 impair its interaction with Sec63 and cause defects in membrane insertion and C-terminal translocation of both single- and multi-spanning membrane proteins.\",\n      \"method\": \"Yeast Sec62 N-terminal domain mutants; co-IP to assess Sec62–Sec63 interaction; systematic analysis of single and multi-spanning membrane proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutant analysis combined with interaction assay and multiple substrate topology analysis\",\n      \"pmids\": [\"25097231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The SRP receptor (SRα) switches the Sec61 translocase from Sec62-dependent to SRP-dependent translocation by physically displacing Sec62 from Sec61; the charged linker region of SRα (between longin and GTPase domains) mediates this displacement.\",\n      \"method\": \"Truncation variants of SRα; crosslinking; in vitro translocation assays; co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution-style crosslinking and translocation assays with domain truncations; mechanistic link between SRP receptor and Sec62 displacement\",\n      \"pmids\": [\"26634806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sec62 and Sec63 are stabilized within the Sec61 translocon when the nascent polypeptide encounters a delay in translocation initiation (e.g., by passenger domain folding); the engaged nascent chain controls translocon composition, with Sec62/63-containing complexes forming when translocation initiation is slow.\",\n      \"method\": \"Ribosome-nascent chain complex isolation; co-immunoprecipitation of translocon components at defined translocation stages using model substrate preprolactin\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical capture of defined cotranslational intermediates with multiple substrates and multiple translocon components; strong mechanistic correlation\",\n      \"pmids\": [\"25801167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sec62 acts as an ER-resident autophagy receptor (recovER-phagy receptor) during recovery from ER stress, selectively delivering excess ER components to the autolysosomal system; this function requires a conserved LC3-interacting region (LIR) in the C-terminal cytosolic domain of Sec62, which is dispensable for its protein translocation function.\",\n      \"method\": \"Live-cell imaging; loss-of-function studies; LIR motif mutagenesis; autophagy flux assays in ER stress recovery conditions\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — LIR mutagenesis separating two distinct functions plus multiple imaging and flux assays; high citation count, widely replicated concept\",\n      \"pmids\": [\"27749824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human Sec62/Sec63-dependent ER import substrates share signal peptides with longer but less hydrophobic h-regions and lower C-region polarity; a slowly-gating signal peptide combined with a downstream positively-charged amino acid cluster is decisive for Sec62/Sec63 requirement, which may involve Sec62/Sec63 supporting Sec61-channel opening via direct interaction with the N-terminal cytosolic peptide of Sec61α or via BiP recruitment to ER-lumenal loop 7.\",\n      \"method\": \"Unbiased proteomics (in-cell protein import assay); siRNA knockdown; signal peptide mutagenesis; identification of 22 novel substrates\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased proteomics substrate identification combined with mutagenesis and multiple mechanistic follow-up experiments\",\n      \"pmids\": [\"32133789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of Sec61-Sec62-Sec63 complexes from S. cerevisiae and T. lanuginosus show that Sec62 and Sec63 activate Sec61 for post-translational translocation in a stepwise/hierarchical manner: Sec63 first partially opens the Sec61 lateral gate through cytosolic and luminal domain interactions, then Sec62 opens the translocation pore by displacing the plug domain; Sec62 may also prevent lipid invasion through the open lateral gate.\",\n      \"method\": \"Cryo-electron microscopy structure determination; molecular dynamics simulations; mutagenesis of Sec61–Sec63 interface residues\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with multiple complex variants plus MD simulations; mechanistic model of stepwise gating directly validated by mutagenesis\",\n      \"pmids\": [\"33398175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATG9A acetylation status in the ER lumen controls induction of reticulophagy, and this requires ATG9A to engage SEC62 (as well as FAM134B) on the cytosolic side of the ER membrane.\",\n      \"method\": \"ATG9A interactome analysis in two mouse models of AT-1 dysregulation; co-immunoprecipitation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interactome/co-IP in mouse models; identifies SEC62 as ATG9A partner in reticulophagy but functional follow-up is limited\",\n      \"pmids\": [\"33870132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sec62 promotes gastric cancer metastasis by binding to LC3II and activating autophagy via the PERK/ATF4 pathway, with concomitant FIP200/Beclin-1/Atg5 activation; autophagy blockage abolishes Sec62-driven cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation of Sec62 with LC3II; Western blot for UPR/autophagy markers; transwell migration/invasion assays; xenograft models; autophagy inhibitor rescue experiments\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional rescue experiments linking Sec62–LC3II interaction to autophagy-dependent metastasis; single lab\",\n      \"pmids\": [\"35165763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC62 binds DDX3X, and DDX3X is essential for TLOC1/SEC62-induced oncogenic transformation (anchorage-independent growth); this interaction was identified by proteomic studies.\",\n      \"method\": \"Proteomic interaction studies (pulldown/MS); loss-of-function genetic screen; gain-of-function transformation assays\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proteomics-identified interaction validated by loss-of-function; mechanistic link to transformation established\",\n      \"pmids\": [\"23764425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC62 binds β-catenin and inhibits its degradation by competitively disrupting the interaction between β-catenin and APC, thereby preventing assembly of the β-catenin destruction complex and activating Wnt/β-catenin signaling in colorectal cancer cells.\",\n      \"method\": \"GST pull-down; co-immunoprecipitation; Western blot for β-catenin destruction complex components; siRNA loss-of-function with phenotypic readouts\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GST pulldown plus co-IP plus competitive disruption assay; single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"33858476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEC62 activates the MAPK/JNK signaling pathway, leading to ATF2-mediated transcriptional upregulation of the lncRNA UCA1, which promotes colorectal cancer metastasis; blocking or activating JNK suppresses or enhances Sec62-mediated metastasis.\",\n      \"method\": \"RNA sequencing; rescue experiments with JNK inhibitor/agonist; luciferase reporter assay; ChIP assay; transwell/wound healing assays\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement by epistasis (JNK inhibitor rescue) plus ChIP and reporter assay; single lab\",\n      \"pmids\": [\"36200182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Molecular dynamics simulations starting from cryo-EM structures show that the presence of Sec62 alters the conformational dynamics of the Sec61 lateral gate, plug, and pore region; without Sec62, the luminal side of the lateral gate closes toward the apo state, while with Sec62 bound it adopts a wider (active) conformation.\",\n      \"method\": \"Molecular dynamics simulations based on cryo-EM structures of Sec61 with/without Sec62\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational MD simulation only, no experimental validation of conformational changes\",\n      \"pmids\": [\"36116515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC62 directly interacts with TRPM4 and promotes TRPM4 ubiquitination and proteasomal degradation; the compound cinobufagin binds SEC62 and disrupts the SEC62–TRPM4 interaction, thereby stabilizing TRPM4 and inducing necrosis by sodium overload in bortezomib-resistant myeloma cells.\",\n      \"method\": \"LiP-MS, molecular docking, MST and CETSA target engagement assays; SPR for SEC62–TRPM4 interaction; immunoprecipitation for ubiquitination; SEC62 knockdown validation\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple target engagement methods (MST, CETSA, SPR) plus ubiquitination assay; single lab but orthogonal biochemical methods\",\n      \"pmids\": [\"40839992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC62-dependent ER-phagy in vascular endothelial cells promotes monocyte–endothelial cell adhesion and atherosclerosis; apelin-13 upregulates SEC62 to induce ER-phagy, and vascular endothelial cell-specific SEC62 deletion reduces atherosclerotic plaques in APOE-/- mice. Mechanistically, UBL4A mediates ubiquitin-like modification of ALDH1L1 at lysine-812, promoting ALDH1L1 insertion into the ER membrane and SEC62-dependent ER-phagy.\",\n      \"method\": \"siRNA knockdown; cell-specific knockout in APOE-/- mice with high-fat diet; co-immunoprecipitation; ubiquitination assay with lysine mutant\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic KO with defined phenotype plus biochemical interaction/ubiquitination assays; single lab\",\n      \"pmids\": [\"39930135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC62 at mitochondria-associated membranes (MAMs) interacts directly with ATAD3B and suppresses ATAD3B expression, causing defective mitophagy, increased mitochondrial ROS, and inflammation, thereby driving MASH progression; hepatocyte-specific SEC62 overexpression worsens and SEC62 knockout ameliorates MASH phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (SEC62–ATAD3B interaction); hepatocyte-specific KO and overexpression mouse models; mitophagy and ROS assays\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus bidirectional in vivo genetic manipulation with defined mechanistic readouts; single lab\",\n      \"pmids\": [\"42001994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC62-mediated ER-phagy is deficient in Alzheimer's disease neurons; AAV-driven overexpression of SEC62 in 5×FAD mouse brains reduces Aβ plaque deposition, neuroinflammation, and cognitive impairment, establishing SEC62 ER-phagy as a mechanism for ER quality control relevant to AD pathology.\",\n      \"method\": \"Intrathecal AAV injection in 5×FAD mice; behavioral assays; immunostaining for Aβ and neuroinflammation markers; iPSC-derived neurons from AD patients\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function in disease model with multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"42026868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The intrinsically disordered regions (IDRs) of SEC62 exposed at the cytoplasmic face of the ER membrane (not its transmembrane domains) drive ER fragmentation during ER-phagy; the transmembrane domains determine sub-compartmental distribution but are dispensable for fragmentation.\",\n      \"method\": \"Domain swap experiments; live-cell imaging of ER fragmentation; loss-of-function and gain-of-function constructs for IDR and transmembrane domains\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2-3 — preprint; mechanistic domain dissection with imaging but not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.06.18.599470\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEC62 encodes a conserved ER membrane protein that (1) functions as a component of the Sec61–Sec62–Sec63 post-translational translocation channel, where cryo-EM structures show Sec62 opens the Sec61 pore by displacing its plug domain in a hierarchical manner with Sec63, and whose engagement with specific substrates is governed by signal peptide hydrophobicity and downstream charged residues; (2) serves as an ER-phagy (recovER-phagy) receptor through a C-terminal LIR motif that engages LC3 to selectively deliver excess ER to autolysosomes during stress recovery; (3) regulates cytosolic Ca2+ homeostasis via a Ca2+-sensitive direct interaction with the Sec61 channel; and (4) participates in oncogenic signaling including Wnt/β-catenin pathway activation (by binding and stabilizing β-catenin) and MAPK/JNK-driven metastasis promotion, while its expression level is controlled by METTL3-mediated m6A modification of its mRNA.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEC62 is a conserved ER membrane protein that functions as a core component of the Sec61–Sec62–Sec63 post-translational translocation channel and as an ER-phagy receptor, linking ER protein import to ER quality control. In the translocation channel, Sec62 opens the Sec61 pore by displacing its plug domain in a hierarchical mechanism with Sec63, and is specifically required for post-translational import of substrates with less hydrophobic signal peptides, including small secretory proteins; the SRP receptor switches the translocon from Sec62-dependent to SRP-dependent mode by physically displacing Sec62 from Sec61 [PMID:33398175, PMID:22375059, PMID:26634806]. Independent of its translocation role, Sec62 acts as a selective ER-phagy (recovER-phagy) receptor during ER stress recovery through a C-terminal LC3-interacting region that recruits autophagic machinery, a function with physiological consequences in atherosclerosis, neurodegeneration, and liver disease [PMID:27749824, PMID:39930135, PMID:42026868]. SEC62 additionally regulates ER Ca²⁺ leak through Ca²⁺-sensitive interaction with Sec61 and promotes oncogenic signaling by stabilizing β-catenin against destruction-complex-mediated degradation and by activating the MAPK/JNK pathway [PMID:24304694, PMID:33858476, PMID:36200182].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of SEC62 as an ER membrane component required for post-translational protein translocation established its fundamental cellular role, resolving whether the translocation defect was membrane-intrinsic or cytosolic.\",\n      \"evidence\": \"In vitro translocation assay with sec62 mutant membranes/cytosol fractionation in yeast\",\n      \"pmids\": [\"2687286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural information on SEC62\", \"Mammalian ortholog not yet identified\", \"Mechanism of SEC62 action at the translocon unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstration that mammalian Sec62 physically associates with Sec61 and Sec63 in a ribosome-free complex established the conservation of the post-translational translocation machinery from yeast to mammals.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and biochemical fractionation of mammalian ER membranes\",\n      \"pmids\": [\"10799540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate specificity of the mammalian complex unknown\", \"Whether Sec62 has gained new functions in mammals unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that human Sec62 can interact with the ribosomal tunnel exit raised the possibility that mammalian Sec62 has acquired cotranslational roles beyond its conserved post-translational function.\",\n      \"evidence\": \"Co-immunoprecipitation of Sec62 with ribosomes in human cells\",\n      \"pmids\": [\"20071467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of ribosome interaction for cotranslational transport not demonstrated\", \"No structural detail of this interface\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Systematic substrate analysis established that Sec62 is specifically required for post-translational (not cotranslational) ER import in mammalian cells, particularly for small secretory proteins with N-terminal signal sequences, revealing SEC62 as a fail-safe for the SRP pathway.\",\n      \"evidence\": \"siRNA knockdown in HeLa cells with in vitro translocation assays across multiple substrate classes; SRP pathway impairment combined with SEC62 RNAi\",\n      \"pmids\": [\"22375059\", \"22648169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full client proteome not defined\", \"Signal peptide features dictating Sec62 dependence not characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CK2 phosphorylation of Sec63 was shown to enhance its binding to Sec62, revealing a regulatory input that controls assembly of the functional translocon.\",\n      \"evidence\": \"Phosphorylation mapping with CK2 and co-immunoprecipitation of Sec62–Sec63\",\n      \"pmids\": [\"23287549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of CK2-mediated regulation not tested\", \"Whether phosphorylation affects translocation efficiency directly unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two discoveries expanded SEC62's roles: Sec62 was found to regulate signal anchor protein orientation during membrane insertion, and to regulate ER Ca²⁺ leak through a Ca²⁺-sensitive direct interaction with Sec61.\",\n      \"evidence\": \"Yeast Sec62 mutant analysis with model membrane proteins of varying topology; SPR interaction analysis and Ca²⁺ imaging with SEC62 siRNA depletion in human cells\",\n      \"pmids\": [\"23632075\", \"24304694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of Ca²⁺-sensitive Sec62–Sec61 interaction unknown\", \"Whether Ca²⁺ regulation and translocation functions are separable unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The SRP receptor was shown to physically displace Sec62 from Sec61, establishing the molecular switch mechanism between post-translational and cotranslational translocation modes, and Sec62/63 were found to be recruited when translocation initiation is delayed.\",\n      \"evidence\": \"Crosslinking and translocation assays with SRα truncation variants; ribosome-nascent chain complex isolation with co-IP of translocon components\",\n      \"pmids\": [\"26634806\", \"25801167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SRα-mediated Sec62 displacement not resolved\", \"How translocation kinetics regulate Sec62/63 recruitment mechanistically unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery that Sec62 functions as a selective ER-phagy receptor (recovER-phagy) through its C-terminal LIR motif — independent of its translocation role — revealed a second major function for this protein in ER homeostasis.\",\n      \"evidence\": \"LIR motif mutagenesis separating translocation and autophagy functions; autophagy flux assays during ER stress recovery\",\n      \"pmids\": [\"27749824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo selectivity mechanism for ER-phagy not defined\", \"How SEC62-mediated ER-phagy is initiated and terminated unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Unbiased proteomics identified the signal peptide code for Sec62/Sec63 dependence — longer, less hydrophobic h-regions plus downstream positively charged residues — defining the substrate selection rules for this translocation pathway.\",\n      \"evidence\": \"In-cell protein import assay with siRNA knockdown; signal peptide mutagenesis across 22 novel substrates\",\n      \"pmids\": [\"32789789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How signal peptide features mechanistically engage Sec62/Sec63 to open Sec61 not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM structures of the Sec61–Sec62–Sec63 complex revealed the stepwise gating mechanism: Sec63 first partially opens the Sec61 lateral gate, then Sec62 displaces the plug domain to open the pore, resolving the long-standing question of how post-translational translocation is activated.\",\n      \"evidence\": \"Cryo-EM structures from S. cerevisiae and T. lanuginosus with mutagenesis validation and MD simulations\",\n      \"pmids\": [\"33398175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of a substrate-engaged complex not available\", \"Lipid-blocking role of Sec62 at the lateral gate not experimentally validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies established SEC62 as an oncogenic factor acting through diverse signaling pathways: binding and stabilizing β-catenin to activate Wnt signaling, activating MAPK/JNK to drive metastasis, and interacting with DDX3X to promote cellular transformation.\",\n      \"evidence\": \"GST pulldown and co-IP for β-catenin interaction; JNK inhibitor rescue and ChIP assays; proteomic identification of DDX3X interaction with transformation assays\",\n      \"pmids\": [\"33858476\", \"36200182\", \"23764425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an ER membrane protein accesses cytoplasmic/nuclear β-catenin mechanistically unresolved\", \"Whether oncogenic functions depend on translocation or ER-phagy activities unknown\", \"Single-lab findings for each pathway\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SEC62-mediated ER-phagy was shown to have broad pathophysiological relevance: promoting atherosclerosis in endothelial cells, being deficient in Alzheimer's disease neurons (where its restoration reduces Aβ pathology), and interacting with ATAD3B at MAMs to suppress mitophagy and drive MASH.\",\n      \"evidence\": \"Endothelial-specific SEC62 KO in APOE−/− mice; AAV-SEC62 overexpression in 5×FAD mice; hepatocyte-specific SEC62 KO and overexpression with mitophagy assays\",\n      \"pmids\": [\"39930135\", \"42026868\", \"42001994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAM localization represents a distinct pool from ER-phagy receptor pool unclear\", \"Upstream signals controlling SEC62 expression in disease contexts incompletely mapped\", \"Single-lab studies for each disease model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SEC62 was found to promote TRPM4 ubiquitination and proteasomal degradation through direct interaction, linking SEC62 to ion channel proteostasis and drug resistance in myeloma.\",\n      \"evidence\": \"SPR, MST, and CETSA target engagement assays; ubiquitination immunoprecipitation; SEC62 knockdown\",\n      \"pmids\": [\"40839992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating TRPM4 ubiquitination through SEC62 not identified\", \"Whether this represents a general SEC62 function in membrane protein quality control unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structure of a substrate-engaged Sec61–Sec62–Sec63 complex, how SEC62 transitions between its translocation and ER-phagy receptor functions, the mechanism by which an ER membrane protein activates cytoplasmic signaling pathways (Wnt, MAPK/JNK), and the structural basis by which SEC62's intrinsically disordered regions drive ER membrane fragmentation during ER-phagy.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No substrate-engaged cryo-EM structure\", \"Functional switching mechanism between translocation and ER-phagy roles uncharacterized\", \"Structural basis of ER fragmentation by SEC62 IDRs not peer-review validated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 9, 13]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [11, 15, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 17, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 3, 11, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 3, 4, 12, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 14, 15, 21, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 12]}\n    ],\n    \"complexes\": [\n      \"Sec61-Sec62-Sec63 translocon\"\n    ],\n    \"partners\": [\n      \"SEC61A1\",\n      \"SEC63\",\n      \"LC3\",\n      \"CTNNB1\",\n      \"DDX3X\",\n      \"TRPM4\",\n      \"ATAD3B\",\n      \"ATG9A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}