TMEM192

TMEM192 is an integral lysosomal membrane protein that functions as a damage-responsive signal for lysophagy and participates in autophagy regulation. It is a four-pass transmembrane protein that forms homodimers via a C-terminal Cys266 disulfide bond, is targeted to late endosomes/lysosomes through two N-terminal DXXLL-type dileucine motifs, and marks a specific subpopulation of late endosomes/lysosomes distinct from LAMP1/LAMP2-ubiquitous populations (PMID:21143193, PMID:20370317, PMID:39485275). Upon lysosomal damage, TMEM192 is ubiquitinated by SCF-FBXO27 and by SCF-FBXO3 downstream of TBK1 phosphorylation, and ubiquitinated TMEM192 is recognized by the autophagy receptor TAX1BP1 to drive lysophagic clearance of damaged lysosomes (PMID:28743755, PMID:40083080). TMEM192 also interacts with the tumor suppressor TIG1 to promote Beclin-1- and LC3-dependent autophagy, and its abundant, stable residence on the lysosomal membrane has been widely exploited as an anchor for immunoprecipitation-based isolation of intact lysosomes from cell lines and primary clinical material (PMID:27989102, PMID:31738065, PMID:39724071).

1. 2007 Medium

   Establishing TMEM192 as a bona fide lysosomal membrane protein resolved the cellular compartment for this previously uncharacterized open reading frame.

   Evidence Mass spectrometry of purified placental lysosomal membranes with fluorescent-tag confirmation in HeLa cells

   PMID:17897319

   Open questions at the time

   • No functional role assigned
   • Single proteomics study without genetic validation
   • Membrane topology not determined
2. 2010 High

   Demonstrating that TMEM192 is a non-glycosylated four-pass transmembrane homodimer established its fundamental biochemical architecture.

   Evidence Co-immunoprecipitation, non-reducing SDS-PAGE, Percoll gradient co-sedimentation with LAMP-2 and cathepsin D

   PMID:20370317

   Open questions at the time

   • Dimerization residue not yet mapped
   • Functional consequence of dimerization unknown
   • Targeting signals not identified
3. 2011 High

   Mapping the two DXXLL dileucine targeting motifs and identifying Cys266 as the interchain disulfide residue resolved how TMEM192 reaches lysosomes and how it dimerizes.

   Evidence CD4 chimeric constructs, site-directed mutagenesis of dileucine motifs and Cys266, immunogold labeling, proteinase protection assay

   PMID:21143193

   Open questions at the time

   • Adaptor protein(s) recognizing the dileucine motifs not identified
   • Functional role of TMEM192 at the lysosome still unknown
   • Whether dimerization is required for function untested
4. 2012 Medium

   Showing that TMEM192 knockdown induces autophagy and ATG7-dependent apoptosis provided the first functional link between TMEM192 and autophagic/cell death pathways.

   Evidence siRNA knockdown in HepG2 cells, LC3-II immunoblotting, epistasis with ATG7 co-knockdown

   PMID:22736246

   Open questions at the time

   • Mechanism by which TMEM192 loss triggers autophagy not defined
   • Phenotype observed only in one cancer cell line
   • In vivo relevance not tested
5. 2016 Medium

   Identification of TIG1 as a TMEM192-interacting partner that requires TMEM192 for autophagy induction linked TMEM192 to a tumor suppressor signaling axis at lysosomes.

   Evidence Yeast two-hybrid, co-immunoprecipitation, fluorescence co-localization, siRNA knockdown with Beclin-1/LC3-B readout

   PMID:27989102

   Open questions at the time

   • Direct binding interface not mapped
   • Downstream signaling from TIG1-TMEM192 not characterized
   • Single laboratory finding
6. 2017 High

   Two key advances: TMEM192 was identified as a substrate of SCF-FBXO27-mediated ubiquitination upon lysosomal damage, and TMEM192-knockout mice showed normal basal lysosomal function, indicating context-dependent rather than housekeeping roles.

   Evidence FBXO27 overexpression with ubiquitination/mass spectrometry screen; TMEM192−/− mouse with histopathology, autophagy, and exocytosis assays

   PMID:28504966 PMID:28743755

   Open questions at the time

   • Damage-specific lysophagy phenotype not tested in knockout
   • Redundancy with other lysosomal membrane proteins not addressed
   • FBXO27-TMEM192 interaction mechanism not defined
7. 2019 High

   Systematic benchmarking of TMEM192-based LysoIP demonstrated that its stable, abundant lysosomal residence enables 118-fold enrichment, establishing a widely adopted organelle isolation technology.

   Evidence Comparative immunoprecipitation of 3×HA-TMEM192 vs. sucrose gradient and SPION methods, data-independent acquisition mass spectrometry

   PMID:31738065

   Open questions at the time

   • Whether TMEM192-tagged lysosomes represent the full lysosome population or a subpopulation not assessed
   • Potential overexpression artifacts not excluded
8. 2024 High

   Super-resolution imaging revealed TMEM192 marks a specific late endosome/lysosome subpopulation distinct from LAMP1/LAMP2-positive vesicles, and tagless immunoprecipitation of endogenous TMEM192 enabled native lysosome isolation from clinical samples.

   Evidence Multiplexed DNA-PAINT single-organelle imaging; tagless IP with multi-omics from PBMCs and iPSC-derived neurons

   PMID:39485275 PMID:39724071

   Open questions at the time

   • Functional significance of TMEM192-specific subpopulation unknown
   • Whether subpopulation identity varies across tissues not established
9. 2025 Medium

   Delineation of the TBK1→FBXO3→TMEM192 ubiquitination→TAX1BP1 recognition axis completed the lysophagy signaling cascade from kinase activation to autophagic receptor engagement.

   Evidence TBK1 kinase assay, FBXO3-TMEM192 co-immunoprecipitation, ubiquitination assay, lysophagic flux measurement with loss-of-function perturbation

   PMID:40083080

   Open questions at the time

   • Specific ubiquitination sites on TMEM192 not mapped
   • Relative contributions of FBXO27 vs. FBXO3 pathways in vivo not distinguished
   • Single study awaiting independent replication

• The physiological function of TMEM192 beyond damage-induced lysophagy remains undefined — its role in unstressed conditions, the significance of its subpopulation-restricted distribution, and whether its dimerization is functionally required are unresolved.
• No non-redundant basal phenotype identified in knockout animals
• Structural basis of TMEM192 interactions not determined
• Relationship between TMEM192 subpopulation identity and lysophagy competence unknown