Affinage

TMEM192

Transmembrane protein 192 · UniProt Q8IY95

Length
271 aa
Mass
30.9 kDa
Annotated
2026-06-10
29 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Medium

    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

    PMID:17897319

    Open questions at the time
    • Relied on tagged overexpression for localization
    • No topology or function defined
    • No endogenous protein detection
  2. 2010 High

    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

    PMID:20370317

    Open questions at the time
    • Dimer interface residue not yet mapped
    • Functional consequence of dimerization unknown
    • Targeting determinants not defined
  3. 2011 High

    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

    PMID:21143193

    Open questions at the time
    • Trafficking adaptor recognizing the dileucine motifs not identified
    • Functional role of dimerization still unresolved
  4. 2012 Medium

    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

    PMID:22736246

    Open questions at the time
    • Molecular mechanism connecting TMEM192 loss to autophagy induction unknown
    • Restricted to one cancer cell line
    • No in vivo confirmation of phenotype
  5. 2016 Medium

    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

    PMID:27989102

    Open questions at the time
    • No in vitro reconstitution of the interaction
    • Direct vs indirect interaction not resolved
    • Mechanism of how TMEM192 transduces TIG1 signal unknown
  6. 2017 Medium

    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

    PMID:28504966 PMID:28743755

    Open questions at the time
    • Ubiquitination sites not mapped
    • Functional consequence of FBXO27-mediated ubiquitination on lysophagy not established
    • Tissue-specific proteolytic fragment function unknown
  7. 2019 Medium

    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

    PMID:31738065

    Open questions at the time
    • Required transgenic tag expression
    • Does not address endogenous TMEM192 function
  8. 2024 Medium

    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

    PMID:39485275 PMID:39724071

    Open questions at the time
    • Basis for TMEM192 organelle subpopulation specificity unknown
    • Functional distinction of TMEM192-positive LELs not defined
  9. 2025 Medium

    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

    PMID:40083080

    Open questions at the time
    • Relative contributions of FBXO27 vs FBXO3 to lysophagy not clarified
    • Ubiquitin chain type and acceptor sites not defined
    • Single-lab epistasis without structural validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No defined molecular activity for the protein
  • Mechanism connecting TMEM192 to autophagy induction unknown
  • Functional identity of TMEM192-marked LEL subpopulation undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005764 lysosome 5 GO:0005768 endosome 2
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-392499 Metabolism of proteins 2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. Organellar proteomics of placental lysosomal membranes; fluorescent tag fusion protein expression in HeLa cells with colocalization Traffic (Copenhagen, Denmark) Medium 17897319
2010 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. 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 Biological chemistry High 20370317
2011 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. CD4 chimeric construct mutagenesis; site-directed mutagenesis of dileucine motifs and cysteine residues; immunogold electron microscopy; proteinase protection assay; immunofluorescence The Biochemical journal High 21143193
2016 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. Yeast two-hybrid; co-immunoprecipitation/colocalization; siRNA knockdown with autophagy marker readout (Beclin-1, LC-3B) Molecules and cells Medium 27989102
2012 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. siRNA knockdown; immunoblotting for LC3-II; Atg7 siRNA epistasis; apoptosis assays Oncology reports Medium 22736246
2017 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. Ubiquitination screen upon lysosomal damage; FBXO27 overexpression with ubiquitination assay; mass spectrometry identification Proceedings of the National Academy of Sciences of the United States of America Medium 28743755
2017 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. TMEM192 knockout mouse generation; histopathological, ultrastructural (EM), and biochemical analyses; lysosomal exocytosis assay; pH-dependent protease inhibition experiments Oncotarget Medium 28504966
2019 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). Comparative lysosome enrichment by immunoprecipitation of 3xHA-TMEM192 vs. SPIONs, centrifugation, and sucrose gradient; data-independent acquisition proteomics Journal of proteome research Medium 31738065
2024 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. Multiplexed quantitative DNA-PAINT super-resolution imaging of seven LEL membrane proteins on individual organelles The Journal of cell biology Medium 39485275
2024 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. Immunoprecipitation of endogenous TMEM192 from clinical blood samples and iPSC neurons; lysosomal integrity assessment; metabolomic and proteomic profiling The Journal of clinical investigation Medium 39724071
2025 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. Genetic and biochemical perturbation of TBK1, FBXO3, TMEM192, and TAX1BP1; lysophagy flux assays; co-immunoprecipitation; ubiquitination assays Autophagy Medium 40083080

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Integral and associated lysosomal membrane proteins. Traffic (Copenhagen, Denmark) 163 17897319
2017 Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences of the United States of America 117 28743755
2020 Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis. Autophagy 100 32070194
2010 Molecular characterisation of 'transmembrane protein 192' (TMEM192), a novel protein of the lysosomal membrane. Biological chemistry 48 20370317
2019 Systematic Comparison of Strategies for the Enrichment of Lysosomes by Data Independent Acquisition. Journal of proteome research 31 31738065
2024 Heterogeneity of late endosome/lysosomes shown by multiplexed DNA-PAINT imaging. The Journal of cell biology 27 39485275
2011 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. The Biochemical journal 24 21143193
2022 KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity. Autophagy 20 35266843
2016 Tazarotene-Induced Gene 1 Enhanced Cervical Cell Autophagy through Transmembrane Protein 192. Molecules and cells 16 27989102
2024 Endo-IP and lyso-IP toolkit for endolysosomal profiling of human-induced neurons. Proceedings of the National Academy of Sciences of the United States of America 15 39636867
2012 Lysosomal membrane protein TMEM192 deficiency triggers crosstalk between autophagy and apoptosis in HepG2 hepatoma cells. Oncology reports 15 22736246
2023 Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer. Autophagy 13 37772772
2024 Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples. The Journal of clinical investigation 12 39724071
2017 Functional characterization of the lysosomal membrane protein TMEM192 in mice. Oncotarget 12 28504966
2019 Exome sequencing in genomic regions related to racing performance of Quarter Horses. Journal of applied genetics 9 30666567
2024 Two-Step Enrichment Facilitates Background Reduction for Proteomic Analysis of Lysosomes. Journal of proteome research 8 38967832
2025 Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction. Autophagy 6 41103078
2022 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. Gene 6 36470485
2024 Multiplexed DNA-PAINT Imaging of the Heterogeneity of Late Endosome/Lysosome Protein Composition. bioRxiv : the preprint server for biology 4 38562776
2024 Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes. Journal of visualized experiments : JoVE 3 39400187
2026 Measuring lysosome damage and lysophagy in vivo. Autophagy 1 41485143
2025 Purifying and profiling lysosomes to expand understanding of lysosomal dysfunction-associated diseases. The Journal of clinical investigation 1 39959975
2025 The TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for lysophagy. Autophagy 1 40083080
2024 Endo-IP and Lyso-IP Toolkit for Endolysosomal Profiling of Human Induced Neurons. bioRxiv : the preprint server for biology 1 39386502
2022 The exploration of new biomarkers for oral cancer through the ceRNA network and immune microenvironment analysis. Medicine 1 36626444
2026 TGFB-inducible VASN (vasorin) promotes lysosomal acidification. Autophagy 0 41630427
2026 Co-option of Lysosomal Machinery for Sponge Biosilicification. bioRxiv : the preprint server for biology 0 42094339
2026 Byakangelicin alleviates metabolic dysfunction-associated steatohepatitis by selective inhibition of a non-canonical MTORC1 signaling pathway. Autophagy 0 42152469
2025 Temporally integrated multiomics analysis elucidates intricate regulatory mechanisms of ASFV in a wild boar lung-derived clonal cell line. Veterinary research 0 41088433

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