{"gene":"TMEM192","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2007,"finding":"TMEM192 (encoded by LOC201931/FLJ38482) was identified as an integral lysosomal membrane protein; fusion protein constructs expressed in HeLa cells localized to lysosomal organelles, establishing lysosomal membrane residence.","method":"Organellar proteomics of placental lysosomal membranes; fluorescent tag fusion protein expression in HeLa cells with colocalization","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fluorescent tag localization in HeLa cells plus proteomic identification; two orthogonal methods, single lab","pmids":["17897319"],"is_preprint":false},{"year":2010,"finding":"TMEM192 localizes to lysosomal/late endosomal membranes (confirmed for both overexpressed and endogenous protein), lacks N-glycosylation, and forms homodimers linked by interchain disulfide bridges, as demonstrated by co-immunoprecipitation and comparison of reduced vs. non-reduced western blots.","method":"Anti-TMEM192 antibody generation; Percoll density gradient centrifugation/immunoblotting; co-immunoprecipitation; reduced vs. non-reduced SDS-PAGE; immunofluorescence colocalization with LAMP-2 and cathepsin D","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, density gradient, immunofluorescence, glycosylation analysis) in a single focused study, replicated by subsequent papers","pmids":["20370317"],"is_preprint":false},{"year":2011,"finding":"Two adjacent N-terminal dileucine motifs (DXXLL-type) are required for TMEM192 targeting to late endosomes/lysosomes; disruption of both motifs misdirects TMEM192 to the plasma membrane, while each single motif is sufficient for correct targeting. Cys266 in the C-terminal cytosolic tail is responsible for intermolecular disulfide bond formation in TMEM192 homodimers; mutation of Cys266 abolishes dimer formation. Immunogold labeling and proteinase protection assays confirmed that both N- and C-termini face the cytosol.","method":"CD4 chimeric construct mutagenesis; site-directed mutagenesis of dileucine motifs and cysteine residues; immunogold electron microscopy; proteinase protection assay; immunofluorescence","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with functional readout (mistargeting), topology confirmed by two orthogonal structural methods (immunogold + proteinase protection), replicates and extends prior co-IP dimer finding","pmids":["21143193"],"is_preprint":false},{"year":2016,"finding":"TMEM192 physically interacts with TIG1 (tazarotene-induced gene 1) isoforms A and B, as identified by yeast two-hybrid and confirmed by colocalization in HtTA cervical cancer cells. Silencing of TMEM192 reduced TIG1-mediated upregulation of autophagy (Beclin-1, LC-3B), placing TMEM192 downstream of TIG1 in autophagy induction.","method":"Yeast two-hybrid; co-immunoprecipitation/colocalization; siRNA knockdown with autophagy marker readout (Beclin-1, LC-3B)","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus colocalization and siRNA phenotype, single lab, two orthogonal methods but no in vitro reconstitution","pmids":["27989102"],"is_preprint":false},{"year":2012,"finding":"Knockdown of TMEM192 in HepG2 hepatoma cells induces autophagy (elevated LC3-II) and subsequent apoptosis via the mitochondrial pathway; blocking Atg7 expression in TMEM192-deficient cells inhibits the increased apoptosis, establishing that TMEM192 loss-induced apoptosis is autophagy-dependent.","method":"siRNA knockdown; immunoblotting for LC3-II; Atg7 siRNA epistasis; apoptosis assays","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Atg7 knockdown rescues apoptosis) plus loss-of-function phenotype, single lab","pmids":["22736246"],"is_preprint":false},{"year":2017,"finding":"TMEM192 is ubiquitinated by the SCF(FBXO27) ubiquitin ligase complex upon lysosomal damage; FBXO27 overexpression increases TMEM192 ubiquitination, implicating TMEM192 as a substrate of SCFFBXO27-mediated lysophagy signaling.","method":"Ubiquitination screen upon lysosomal damage; FBXO27 overexpression with ubiquitination assay; mass spectrometry identification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assay with overexpression validation, single lab, mass spectrometry identification","pmids":["28743755"],"is_preprint":false},{"year":2017,"finding":"In TMEM192-knockout mice, lysosomal morphology, autophagy, and lysosomal exocytosis in MEFs were normal under basal conditions. Murine TMEM192 undergoes proteolytic processing by pH-dependent lysosomal proteases to generate a 17 kDa fragment in a tissue-specific manner (absent in liver). These findings indicate that TMEM192 loss can be compensated in vivo under basal conditions.","method":"TMEM192 knockout mouse generation; histopathological, ultrastructural (EM), and biochemical analyses; lysosomal exocytosis assay; pH-dependent protease inhibition experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with multiple orthogonal analyses; processing mechanism confirmed by protease inhibition; single lab","pmids":["28504966"],"is_preprint":false},{"year":2019,"finding":"3xHA-tagged TMEM192 expressed in cells enables high-efficiency immunoprecipitation-based lysosome enrichment (up to 118-fold enrichment for certain lysosomal proteins vs. whole cell lysate), outperforming centrifugation and sucrose gradient methods; this established TMEM192 as a reliable integral lysosomal membrane anchor for organelle isolation (LysoIP/TMEM-IP methodology).","method":"Comparative lysosome enrichment by immunoprecipitation of 3xHA-TMEM192 vs. SPIONs, centrifugation, and sucrose gradient; data-independent acquisition proteomics","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic quantitative comparison across four methods, single lab, DIA proteomics with enrichment factor quantification","pmids":["31738065"],"is_preprint":false},{"year":2024,"finding":"Super-resolution DNA-PAINT imaging of individual late endosomes/lysosomes (LELs) showed that TMEM192 marks a specific LEL subpopulation rather than being uniformly distributed across all LELs, revealing organelle heterogeneity at single-LEL resolution.","method":"Multiplexed quantitative DNA-PAINT super-resolution imaging of seven LEL membrane proteins on individual organelles","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative super-resolution imaging with multiple protein markers, single lab, published and preprint versions consistent","pmids":["39485275"],"is_preprint":false},{"year":2024,"finding":"Tagless LysoIP using an antibody against endogenous TMEM192 enables rapid immunoprecipitation of intact lysosomes from primary clinical samples (PBMCs from blood) and iPSC-derived neurons without requiring transgenic tag expression; isolated lysosomes were intact and suitable for multimodal omics analyses.","method":"Immunoprecipitation of endogenous TMEM192 from clinical blood samples and iPSC neurons; lysosomal integrity assessment; metabolomic and proteomic profiling","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional validation in primary human samples with integrity controls, single lab, multiple omics readouts","pmids":["39724071"],"is_preprint":false},{"year":2025,"finding":"TBK1-dependent phosphorylation of FBXO3 facilitates FBXO3 interaction with TMEM192, promoting TMEM192 ubiquitination, which is then recognized by the autophagy receptor TAX1BP1 to drive lysophagic flux. Disruption of this TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis significantly reduces lysophagy and causes accumulation of damaged lysosomes.","method":"Genetic and biochemical perturbation of TBK1, FBXO3, TMEM192, and TAX1BP1; lysophagy flux assays; co-immunoprecipitation; ubiquitination assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and co-IP with functional lysophagy readout, single lab, multiple pathway components tested","pmids":["40083080"],"is_preprint":false}],"current_model":"TMEM192 is an integral lysosomal/late endosomal membrane protein with four transmembrane segments and cytosolic N- and C-termini, targeted to lysosomes via two N-terminal DXXLL-type dileucine motifs; it forms homodimers via a C-terminal (Cys266) disulfide bond, undergoes tissue-specific proteolytic processing by lysosomal proteases, is ubiquitinated by SCF(FBXO27) and SCF(FBXO3) upon lysosomal damage (the latter in a TBK1-dependent manner to recruit TAX1BP1 for lysophagy), interacts with TIG1 to promote autophagy, and serves as a widely used endogenous anchor for lysosome immunoprecipitation (LysoIP) to profile lysosomal contents."},"narrative":{"mechanistic_narrative":"TMEM192 is an integral lysosomal/late endosomal membrane protein that contributes to lysosomal quality control and autophagy regulation [PMID:20370317, PMID:40083080]. It is a non-glycosylated, multipass membrane protein with cytosol-facing N- and C-termini; correct delivery to late endosomes/lysosomes requires two adjacent N-terminal DXXLL-type dileucine motifs, and it forms interchain disulfide-linked homodimers through Cys266 in its C-terminal cytosolic tail [PMID:20370317, PMID:21143193]. Functionally, TMEM192 is a substrate for ubiquitin ligase signaling during lysosomal damage: it is ubiquitinated by SCF(FBXO27) and, via TBK1-dependent phosphorylation of FBXO3, by SCF(FBXO3), with the latter modification recognized by the autophagy receptor TAX1BP1 to drive lysophagic clearance of damaged lysosomes [PMID:28743755, PMID:40083080]. TMEM192 also acts downstream of TIG1 to promote autophagy, and its loss in hepatoma cells triggers autophagy-dependent apoptosis, while its loss in mice is compensated under basal conditions [PMID:27989102, PMID:22736246, PMID:28504966]. Exploiting its stable endogenous residence in the lysosomal membrane, TMEM192 serves as the standard anchor for immunoprecipitation-based lysosome isolation (LysoIP), enabling enrichment of intact lysosomes for multi-omic profiling from cell lines and primary clinical samples [PMID:31738065, PMID:39724071].","teleology":[{"year":2007,"claim":"Established that the uncharacterized ORF TMEM192 is a bona fide lysosomal membrane protein, defining its subcellular home.","evidence":"Organellar proteomics of placental lysosomal membranes plus fluorescent fusion colocalization in HeLa cells","pmids":["17897319"],"confidence":"Medium","gaps":["Relied on tagged overexpression for localization","No topology or function defined","No endogenous protein detection"]},{"year":2010,"claim":"Confirmed endogenous lysosomal/late endosomal residence and revealed that TMEM192 is non-glycosylated and forms disulfide-linked homodimers, defining its basic biochemical state.","evidence":"Anti-TMEM192 antibody, Percoll gradient immunoblotting, co-IP, reduced vs non-reduced SDS-PAGE, immunofluorescence with LAMP-2/cathepsin D","pmids":["20370317"],"confidence":"High","gaps":["Dimer interface residue not yet mapped","Functional consequence of dimerization unknown","Targeting determinants not defined"]},{"year":2011,"claim":"Defined the targeting signals and membrane topology, showing two N-terminal dileucine motifs direct lysosomal delivery and Cys266 mediates the homodimer disulfide bond.","evidence":"CD4 chimera and site-directed mutagenesis, immunogold EM, proteinase protection assay","pmids":["21143193"],"confidence":"High","gaps":["Trafficking adaptor recognizing the dileucine motifs not identified","Functional role of dimerization still unresolved"]},{"year":2012,"claim":"Linked TMEM192 to autophagy/apoptosis balance by showing its loss induces autophagy-dependent mitochondrial apoptosis in hepatoma cells.","evidence":"siRNA knockdown with LC3-II immunoblotting and Atg7 epistasis in HepG2 cells","pmids":["22736246"],"confidence":"Medium","gaps":["Molecular mechanism connecting TMEM192 loss to autophagy induction unknown","Restricted to one cancer cell line","No in vivo confirmation of phenotype"]},{"year":2016,"claim":"Placed TMEM192 in an autophagy-inducing pathway as a physical partner and downstream effector of TIG1.","evidence":"Yeast two-hybrid, co-IP/colocalization, and siRNA knockdown with Beclin-1/LC-3B readout in HtTA cells","pmids":["27989102"],"confidence":"Medium","gaps":["No in vitro reconstitution of the interaction","Direct vs indirect interaction not resolved","Mechanism of how TMEM192 transduces TIG1 signal unknown"]},{"year":2017,"claim":"Identified TMEM192 as a ubiquitination substrate during lysosomal damage and showed basal dispensability in vivo, separating its quality-control role from constitutive lysosome maintenance.","evidence":"Ubiquitination/MS screen with FBXO27 overexpression; TMEM192-knockout mouse with EM, exocytosis, and protease-inhibition analyses","pmids":["28743755","28504966"],"confidence":"Medium","gaps":["Ubiquitination sites not mapped","Functional consequence of FBXO27-mediated ubiquitination on lysophagy not established","Tissue-specific proteolytic fragment function unknown"]},{"year":2019,"claim":"Converted TMEM192's stable lysosomal residence into a tool, establishing the tagged LysoIP method for high-efficiency lysosome isolation.","evidence":"Comparative enrichment of 3xHA-TMEM192 IP vs SPIONs, centrifugation, and sucrose gradient with DIA proteomics","pmids":["31738065"],"confidence":"Medium","gaps":["Required transgenic tag expression","Does not address endogenous TMEM192 function"]},{"year":2024,"claim":"Extended the methodology to a tagless, antibody-based LysoIP from primary human samples and revealed that TMEM192 marks a heterogeneous subset of late endosomes/lysosomes.","evidence":"Endogenous TMEM192 IP from PBMCs and iPSC neurons with omics; multiplexed DNA-PAINT super-resolution imaging of single organelles","pmids":["39724071","39485275"],"confidence":"Medium","gaps":["Basis for TMEM192 organelle subpopulation specificity unknown","Functional distinction of TMEM192-positive LELs not defined"]},{"year":2025,"claim":"Resolved a damage-response signaling axis in which TBK1-phosphorylated FBXO3 ubiquitinates TMEM192 for TAX1BP1-driven lysophagy, defining TMEM192 as a key effector of damaged-lysosome clearance.","evidence":"Genetic/biochemical perturbation of TBK1, FBXO3, TMEM192, TAX1BP1 with lysophagy flux, co-IP, and ubiquitination assays","pmids":["40083080"],"confidence":"Medium","gaps":["Relative contributions of FBXO27 vs FBXO3 to lysophagy not clarified","Ubiquitin chain type and acceptor sites not defined","Single-lab epistasis without structural validation"]},{"year":null,"claim":"The endogenous physiological function of TMEM192 beyond serving as a lysophagy substrate and isolation anchor — including the basis for its organelle subpopulation specificity and the molecular link to TIG1-driven autophagy — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined molecular activity for the protein","Mechanism connecting TMEM192 to autophagy induction unknown","Functional identity of TMEM192-marked LEL subpopulation undetermined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1,2,7,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,4,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,10]}],"complexes":[],"partners":["TIG1","FBXO27","FBXO3","TAX1BP1","TBK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IY95","full_name":"Transmembrane protein 192","aliases":[],"length_aa":271,"mass_kda":30.9,"function":"","subcellular_location":"Lysosome membrane; Late endosome","url":"https://www.uniprot.org/uniprotkb/Q8IY95/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM192","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000170088","cell_line_id":"CID001874","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"LAMP2","stoichiometry":10.0},{"gene":"ARL8B","stoichiometry":0.2},{"gene":"LAMP1","stoichiometry":0.2},{"gene":"LAMTOR2","stoichiometry":0.2},{"gene":"SLC12A2","stoichiometry":0.2},{"gene":"MYO1B","stoichiometry":0.2},{"gene":"ACTR6","stoichiometry":0.2},{"gene":"PWWP2A","stoichiometry":0.2},{"gene":"TMEM106B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001874","total_profiled":1310},"omim":[{"mim_id":"620677","title":"TRANSMEMBRANE PROTEIN 192; TMEM192","url":"https://www.omim.org/entry/620677"},{"mim_id":"605090","title":"RETINOIC ACID RECEPTOR RESPONDER 1; RARRES1","url":"https://www.omim.org/entry/605090"},{"mim_id":"603019","title":"CADHERIN 18; CDH18","url":"https://www.omim.org/entry/603019"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endosomes","reliability":"Supported"},{"location":"Lysosomes","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM192"},"hgnc":{"alias_symbol":["FLJ38482"],"prev_symbol":[]},"alphafold":{"accession":"Q8IY95","domains":[{"cath_id":"1.20.120","chopping":"47-209","consensus_level":"high","plddt":86.223,"start":47,"end":209},{"cath_id":"1.20.5","chopping":"230-263","consensus_level":"medium","plddt":86.7935,"start":230,"end":263}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IY95","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IY95-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IY95-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM192","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM192"},"sequence":{"accession":"Q8IY95","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IY95.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IY95/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IY95"}},"corpus_meta":[{"pmid":"17897319","id":"PMC_17897319","title":"Integral and associated lysosomal membrane proteins.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17897319","citation_count":163,"is_preprint":false},{"pmid":"28743755","id":"PMC_28743755","title":"Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28743755","citation_count":117,"is_preprint":false},{"pmid":"32070194","id":"PMC_32070194","title":"Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/32070194","citation_count":100,"is_preprint":false},{"pmid":"20370317","id":"PMC_20370317","title":"Molecular characterisation of 'transmembrane protein 192' (TMEM192), a novel protein of the lysosomal membrane.","date":"2010","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20370317","citation_count":48,"is_preprint":false},{"pmid":"31738065","id":"PMC_31738065","title":"Systematic Comparison of Strategies for the Enrichment of Lysosomes by Data Independent Acquisition.","date":"2019","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/31738065","citation_count":31,"is_preprint":false},{"pmid":"39485275","id":"PMC_39485275","title":"Heterogeneity of late endosome/lysosomes shown by multiplexed DNA-PAINT imaging.","date":"2024","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39485275","citation_count":27,"is_preprint":false},{"pmid":"21143193","id":"PMC_21143193","title":"Two dileucine motifs mediate late endosomal/lysosomal targeting of transmembrane protein 192 (TMEM192) and a C-terminal cysteine residue is responsible for disulfide bond formation in TMEM192 homodimers.","date":"2011","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21143193","citation_count":24,"is_preprint":false},{"pmid":"35266843","id":"PMC_35266843","title":"KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35266843","citation_count":20,"is_preprint":false},{"pmid":"27989102","id":"PMC_27989102","title":"Tazarotene-Induced Gene 1 Enhanced Cervical Cell Autophagy through Transmembrane Protein 192.","date":"2016","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/27989102","citation_count":16,"is_preprint":false},{"pmid":"22736246","id":"PMC_22736246","title":"Lysosomal membrane protein TMEM192 deficiency triggers crosstalk between autophagy and apoptosis in HepG2 hepatoma cells.","date":"2012","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/22736246","citation_count":15,"is_preprint":false},{"pmid":"39636867","id":"PMC_39636867","title":"Endo-IP and lyso-IP toolkit for endolysosomal profiling of human-induced neurons.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39636867","citation_count":15,"is_preprint":false},{"pmid":"37772772","id":"PMC_37772772","title":"Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37772772","citation_count":13,"is_preprint":false},{"pmid":"28504966","id":"PMC_28504966","title":"Functional characterization of the lysosomal membrane protein TMEM192 in mice.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28504966","citation_count":12,"is_preprint":false},{"pmid":"39724071","id":"PMC_39724071","title":"Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39724071","citation_count":12,"is_preprint":false},{"pmid":"30666567","id":"PMC_30666567","title":"Exome sequencing in genomic regions related to racing performance of Quarter Horses.","date":"2019","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30666567","citation_count":9,"is_preprint":false},{"pmid":"38967832","id":"PMC_38967832","title":"Two-Step Enrichment Facilitates Background Reduction for Proteomic Analysis of Lysosomes.","date":"2024","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/38967832","citation_count":8,"is_preprint":false},{"pmid":"41103078","id":"PMC_41103078","title":"Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41103078","citation_count":6,"is_preprint":false},{"pmid":"36470485","id":"PMC_36470485","title":"In silico analysis of genomic landscape of SARS-CoV-2 and its variant of concerns (Delta and Omicron) reveals changes in the coding potential of miRNAs and their target genes.","date":"2022","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/36470485","citation_count":6,"is_preprint":false},{"pmid":"38562776","id":"PMC_38562776","title":"Multiplexed DNA-PAINT Imaging of the Heterogeneity of Late Endosome/Lysosome Protein Composition.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38562776","citation_count":4,"is_preprint":false},{"pmid":"39400187","id":"PMC_39400187","title":"Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes.","date":"2024","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/39400187","citation_count":3,"is_preprint":false},{"pmid":"40083080","id":"PMC_40083080","title":"The TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for lysophagy.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/40083080","citation_count":1,"is_preprint":false},{"pmid":"41485143","id":"PMC_41485143","title":"Measuring lysosome damage and lysophagy in vivo.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41485143","citation_count":1,"is_preprint":false},{"pmid":"39959975","id":"PMC_39959975","title":"Purifying and profiling lysosomes to expand understanding of lysosomal dysfunction-associated diseases.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39959975","citation_count":1,"is_preprint":false},{"pmid":"39386502","id":"PMC_39386502","title":"Endo-IP and Lyso-IP Toolkit for Endolysosomal Profiling of Human Induced Neurons.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39386502","citation_count":1,"is_preprint":false},{"pmid":"36626444","id":"PMC_36626444","title":"The exploration of new biomarkers for oral cancer through the ceRNA network and immune microenvironment analysis.","date":"2022","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36626444","citation_count":1,"is_preprint":false},{"pmid":"41630427","id":"PMC_41630427","title":"TGFB-inducible VASN (vasorin) promotes lysosomal acidification.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41630427","citation_count":0,"is_preprint":false},{"pmid":"41088433","id":"PMC_41088433","title":"Temporally integrated multiomics analysis elucidates intricate regulatory mechanisms of ASFV in a wild boar lung-derived clonal cell line.","date":"2025","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/41088433","citation_count":0,"is_preprint":false},{"pmid":"42094339","id":"PMC_42094339","title":"Co-option of Lysosomal Machinery for Sponge Biosilicification.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42094339","citation_count":0,"is_preprint":false},{"pmid":"42152469","id":"PMC_42152469","title":"Byakangelicin alleviates metabolic dysfunction-associated steatohepatitis by selective inhibition of a non-canonical MTORC1 signaling pathway.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/42152469","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18965,"output_tokens":2972,"usd":0.050737,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10356,"output_tokens":3107,"usd":0.064727,"stage2_stop_reason":"end_turn"},"total_usd":0.115464,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"TMEM192 (encoded by LOC201931/FLJ38482) was identified as an integral lysosomal membrane protein; fusion protein constructs expressed in HeLa cells localized to lysosomal organelles, establishing lysosomal membrane residence.\",\n      \"method\": \"Organellar proteomics of placental lysosomal membranes; fluorescent tag fusion protein expression in HeLa cells with colocalization\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fluorescent tag localization in HeLa cells plus proteomic identification; two orthogonal methods, single lab\",\n      \"pmids\": [\"17897319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TMEM192 localizes to lysosomal/late endosomal membranes (confirmed for both overexpressed and endogenous protein), lacks N-glycosylation, and forms homodimers linked by interchain disulfide bridges, as demonstrated by co-immunoprecipitation and comparison of reduced vs. non-reduced western blots.\",\n      \"method\": \"Anti-TMEM192 antibody generation; Percoll density gradient centrifugation/immunoblotting; co-immunoprecipitation; reduced vs. non-reduced SDS-PAGE; immunofluorescence colocalization with LAMP-2 and cathepsin D\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, density gradient, immunofluorescence, glycosylation analysis) in a single focused study, replicated by subsequent papers\",\n      \"pmids\": [\"20370317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two adjacent N-terminal dileucine motifs (DXXLL-type) are required for TMEM192 targeting to late endosomes/lysosomes; disruption of both motifs misdirects TMEM192 to the plasma membrane, while each single motif is sufficient for correct targeting. Cys266 in the C-terminal cytosolic tail is responsible for intermolecular disulfide bond formation in TMEM192 homodimers; mutation of Cys266 abolishes dimer formation. Immunogold labeling and proteinase protection assays confirmed that both N- and C-termini face the cytosol.\",\n      \"method\": \"CD4 chimeric construct mutagenesis; site-directed mutagenesis of dileucine motifs and cysteine residues; immunogold electron microscopy; proteinase protection assay; immunofluorescence\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with functional readout (mistargeting), topology confirmed by two orthogonal structural methods (immunogold + proteinase protection), replicates and extends prior co-IP dimer finding\",\n      \"pmids\": [\"21143193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TMEM192 physically interacts with TIG1 (tazarotene-induced gene 1) isoforms A and B, as identified by yeast two-hybrid and confirmed by colocalization in HtTA cervical cancer cells. Silencing of TMEM192 reduced TIG1-mediated upregulation of autophagy (Beclin-1, LC-3B), placing TMEM192 downstream of TIG1 in autophagy induction.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation/colocalization; siRNA knockdown with autophagy marker readout (Beclin-1, LC-3B)\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus colocalization and siRNA phenotype, single lab, two orthogonal methods but no in vitro reconstitution\",\n      \"pmids\": [\"27989102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of TMEM192 in HepG2 hepatoma cells induces autophagy (elevated LC3-II) and subsequent apoptosis via the mitochondrial pathway; blocking Atg7 expression in TMEM192-deficient cells inhibits the increased apoptosis, establishing that TMEM192 loss-induced apoptosis is autophagy-dependent.\",\n      \"method\": \"siRNA knockdown; immunoblotting for LC3-II; Atg7 siRNA epistasis; apoptosis assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Atg7 knockdown rescues apoptosis) plus loss-of-function phenotype, single lab\",\n      \"pmids\": [\"22736246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TMEM192 is ubiquitinated by the SCF(FBXO27) ubiquitin ligase complex upon lysosomal damage; FBXO27 overexpression increases TMEM192 ubiquitination, implicating TMEM192 as a substrate of SCFFBXO27-mediated lysophagy signaling.\",\n      \"method\": \"Ubiquitination screen upon lysosomal damage; FBXO27 overexpression with ubiquitination assay; mass spectrometry identification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assay with overexpression validation, single lab, mass spectrometry identification\",\n      \"pmids\": [\"28743755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In TMEM192-knockout mice, lysosomal morphology, autophagy, and lysosomal exocytosis in MEFs were normal under basal conditions. Murine TMEM192 undergoes proteolytic processing by pH-dependent lysosomal proteases to generate a 17 kDa fragment in a tissue-specific manner (absent in liver). These findings indicate that TMEM192 loss can be compensated in vivo under basal conditions.\",\n      \"method\": \"TMEM192 knockout mouse generation; histopathological, ultrastructural (EM), and biochemical analyses; lysosomal exocytosis assay; pH-dependent protease inhibition experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with multiple orthogonal analyses; processing mechanism confirmed by protease inhibition; single lab\",\n      \"pmids\": [\"28504966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"3xHA-tagged TMEM192 expressed in cells enables high-efficiency immunoprecipitation-based lysosome enrichment (up to 118-fold enrichment for certain lysosomal proteins vs. whole cell lysate), outperforming centrifugation and sucrose gradient methods; this established TMEM192 as a reliable integral lysosomal membrane anchor for organelle isolation (LysoIP/TMEM-IP methodology).\",\n      \"method\": \"Comparative lysosome enrichment by immunoprecipitation of 3xHA-TMEM192 vs. SPIONs, centrifugation, and sucrose gradient; data-independent acquisition proteomics\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic quantitative comparison across four methods, single lab, DIA proteomics with enrichment factor quantification\",\n      \"pmids\": [\"31738065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Super-resolution DNA-PAINT imaging of individual late endosomes/lysosomes (LELs) showed that TMEM192 marks a specific LEL subpopulation rather than being uniformly distributed across all LELs, revealing organelle heterogeneity at single-LEL resolution.\",\n      \"method\": \"Multiplexed quantitative DNA-PAINT super-resolution imaging of seven LEL membrane proteins on individual organelles\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative super-resolution imaging with multiple protein markers, single lab, published and preprint versions consistent\",\n      \"pmids\": [\"39485275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tagless LysoIP using an antibody against endogenous TMEM192 enables rapid immunoprecipitation of intact lysosomes from primary clinical samples (PBMCs from blood) and iPSC-derived neurons without requiring transgenic tag expression; isolated lysosomes were intact and suitable for multimodal omics analyses.\",\n      \"method\": \"Immunoprecipitation of endogenous TMEM192 from clinical blood samples and iPSC neurons; lysosomal integrity assessment; metabolomic and proteomic profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional validation in primary human samples with integrity controls, single lab, multiple omics readouts\",\n      \"pmids\": [\"39724071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBK1-dependent phosphorylation of FBXO3 facilitates FBXO3 interaction with TMEM192, promoting TMEM192 ubiquitination, which is then recognized by the autophagy receptor TAX1BP1 to drive lysophagic flux. Disruption of this TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis significantly reduces lysophagy and causes accumulation of damaged lysosomes.\",\n      \"method\": \"Genetic and biochemical perturbation of TBK1, FBXO3, TMEM192, and TAX1BP1; lysophagy flux assays; co-immunoprecipitation; ubiquitination assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and co-IP with functional lysophagy readout, single lab, multiple pathway components tested\",\n      \"pmids\": [\"40083080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM192 is an integral lysosomal/late endosomal membrane protein with four transmembrane segments and cytosolic N- and C-termini, targeted to lysosomes via two N-terminal DXXLL-type dileucine motifs; it forms homodimers via a C-terminal (Cys266) disulfide bond, undergoes tissue-specific proteolytic processing by lysosomal proteases, is ubiquitinated by SCF(FBXO27) and SCF(FBXO3) upon lysosomal damage (the latter in a TBK1-dependent manner to recruit TAX1BP1 for lysophagy), interacts with TIG1 to promote autophagy, and serves as a widely used endogenous anchor for lysosome immunoprecipitation (LysoIP) to profile lysosomal contents.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM192 is an integral lysosomal/late endosomal membrane protein that contributes to lysosomal quality control and autophagy regulation [#1, #10]. It is a non-glycosylated, multipass membrane protein with cytosol-facing N- and C-termini; correct delivery to late endosomes/lysosomes requires two adjacent N-terminal DXXLL-type dileucine motifs, and it forms interchain disulfide-linked homodimers through Cys266 in its C-terminal cytosolic tail [#1, #2]. Functionally, TMEM192 is a substrate for ubiquitin ligase signaling during lysosomal damage: it is ubiquitinated by SCF(FBXO27) and, via TBK1-dependent phosphorylation of FBXO3, by SCF(FBXO3), with the latter modification recognized by the autophagy receptor TAX1BP1 to drive lysophagic clearance of damaged lysosomes [#5, #10]. TMEM192 also acts downstream of TIG1 to promote autophagy, and its loss in hepatoma cells triggers autophagy-dependent apoptosis, while its loss in mice is compensated under basal conditions [#3, #4, #6]. Exploiting its stable endogenous residence in the lysosomal membrane, TMEM192 serves as the standard anchor for immunoprecipitation-based lysosome isolation (LysoIP), enabling enrichment of intact lysosomes for multi-omic profiling from cell lines and primary clinical samples [#7, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that the uncharacterized ORF TMEM192 is a bona fide lysosomal membrane protein, defining its subcellular home.\",\n      \"evidence\": \"Organellar proteomics of placental lysosomal membranes plus fluorescent fusion colocalization in HeLa cells\",\n      \"pmids\": [\"17897319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relied on tagged overexpression for localization\", \"No topology or function defined\", \"No endogenous protein detection\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirmed endogenous lysosomal/late endosomal residence and revealed that TMEM192 is non-glycosylated and forms disulfide-linked homodimers, defining its basic biochemical state.\",\n      \"evidence\": \"Anti-TMEM192 antibody, Percoll gradient immunoblotting, co-IP, reduced vs non-reduced SDS-PAGE, immunofluorescence with LAMP-2/cathepsin D\",\n      \"pmids\": [\"20370317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dimer interface residue not yet mapped\", \"Functional consequence of dimerization unknown\", \"Targeting determinants not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the targeting signals and membrane topology, showing two N-terminal dileucine motifs direct lysosomal delivery and Cys266 mediates the homodimer disulfide bond.\",\n      \"evidence\": \"CD4 chimera and site-directed mutagenesis, immunogold EM, proteinase protection assay\",\n      \"pmids\": [\"21143193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking adaptor recognizing the dileucine motifs not identified\", \"Functional role of dimerization still unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked TMEM192 to autophagy/apoptosis balance by showing its loss induces autophagy-dependent mitochondrial apoptosis in hepatoma cells.\",\n      \"evidence\": \"siRNA knockdown with LC3-II immunoblotting and Atg7 epistasis in HepG2 cells\",\n      \"pmids\": [\"22736246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting TMEM192 loss to autophagy induction unknown\", \"Restricted to one cancer cell line\", \"No in vivo confirmation of phenotype\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed TMEM192 in an autophagy-inducing pathway as a physical partner and downstream effector of TIG1.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP/colocalization, and siRNA knockdown with Beclin-1/LC-3B readout in HtTA cells\",\n      \"pmids\": [\"27989102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the interaction\", \"Direct vs indirect interaction not resolved\", \"Mechanism of how TMEM192 transduces TIG1 signal unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified TMEM192 as a ubiquitination substrate during lysosomal damage and showed basal dispensability in vivo, separating its quality-control role from constitutive lysosome maintenance.\",\n      \"evidence\": \"Ubiquitination/MS screen with FBXO27 overexpression; TMEM192-knockout mouse with EM, exocytosis, and protease-inhibition analyses\",\n      \"pmids\": [\"28743755\", \"28504966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites not mapped\", \"Functional consequence of FBXO27-mediated ubiquitination on lysophagy not established\", \"Tissue-specific proteolytic fragment function unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Converted TMEM192's stable lysosomal residence into a tool, establishing the tagged LysoIP method for high-efficiency lysosome isolation.\",\n      \"evidence\": \"Comparative enrichment of 3xHA-TMEM192 IP vs SPIONs, centrifugation, and sucrose gradient with DIA proteomics\",\n      \"pmids\": [\"31738065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Required transgenic tag expression\", \"Does not address endogenous TMEM192 function\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the methodology to a tagless, antibody-based LysoIP from primary human samples and revealed that TMEM192 marks a heterogeneous subset of late endosomes/lysosomes.\",\n      \"evidence\": \"Endogenous TMEM192 IP from PBMCs and iPSC neurons with omics; multiplexed DNA-PAINT super-resolution imaging of single organelles\",\n      \"pmids\": [\"39724071\", \"39485275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for TMEM192 organelle subpopulation specificity unknown\", \"Functional distinction of TMEM192-positive LELs not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a damage-response signaling axis in which TBK1-phosphorylated FBXO3 ubiquitinates TMEM192 for TAX1BP1-driven lysophagy, defining TMEM192 as a key effector of damaged-lysosome clearance.\",\n      \"evidence\": \"Genetic/biochemical perturbation of TBK1, FBXO3, TMEM192, TAX1BP1 with lysophagy flux, co-IP, and ubiquitination assays\",\n      \"pmids\": [\"40083080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of FBXO27 vs FBXO3 to lysophagy not clarified\", \"Ubiquitin chain type and acceptor sites not defined\", \"Single-lab epistasis without structural validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological function of TMEM192 beyond serving as a lysophagy substrate and isolation anchor — including the basis for its organelle subpopulation specificity and the molecular link to TIG1-driven autophagy — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined molecular activity for the protein\", \"Mechanism connecting TMEM192 to autophagy induction unknown\", \"Functional identity of TMEM192-marked LEL subpopulation undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1, 2, 7, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 4, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TIG1\", \"FBXO27\", \"FBXO3\", \"TAX1BP1\", \"TBK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}