Abstract
The Transmembrane protein 192 (TMEM192) is a lysosomal/late endosomal protein initially discovered by organellar proteomics. TMEM192 exhibits four transmembrane segments with cytosolic N- and C-termini and forms homodimers. Devoid of significant homologies, the molecular function of TMEM192 is currently unknown. Upon TMEM192 knockdown in hepatoma cells, a dysregulation of autophagy and increased apoptosis were reported. Here, we aimed to define the physiological role of TMEM192 by analysing consequences of TMEM192 ablation in mice. Therefore, we compared the biochemical properties of murine TMEM192 to those of the human orthologue. We reveal lysosomal residence of murine TMEM192 and demonstrate ubiquitous tissue expression. In brain, TMEM192 expression was pronounced in the hippocampus but also present in the cortex and cerebellum, as analysed based on a lacZ reporter allele. Murine TMEM192 undergoes proteolytic processing in a tissue-specific manner. Thereby, a 17 kDa fragment is generated which was detected in most murine tissues except liver. TMEM192 processing occurs after lysosomal targeting by pH-dependent lysosomal proteases. TMEM192-/- murine embryonic fibroblasts (MEFs) exhibited a regular morphology of endo-/lysosomes and were capable of performing autophagy and lysosomal exocytosis. Histopathological, ultrastructural and biochemical analyses of all major tissues of TMEM192-/- mice demonstrated normal lysosomal functions without apparent lysosomal storage. Furthermore, the abundance of the major immune cells was comparable in TMEM192-/- and wild type mice. Based on this, we conclude that under basal conditions in vivo the loss of TMEM192 can be efficiently compensated by alternative pathways. Further studies will be required to decipher its molecular function.
Highlights
Lysosomes are central catabolic organelles of eukaryotic cells degrading cell-intrinsic constituents delivered by autophagy as well as exogenous, endocytosed material [1]
The murine protein was detected in its monomeric form in the absence of the reducing agent dithiothreitol (DTT). This excludes the formation of disulphide bridges between different murine Transmembrane protein 192 (TMEM192) monomers
Since we had identified the C-terminal cysteine at position 266 (C266) to be part of the disulphide in human TMEM192, we aligned this part of the two proteins (Figure 1E)
Summary
Lysosomes are central catabolic organelles of eukaryotic cells degrading cell-intrinsic constituents delivered by autophagy as well as exogenous, endocytosed material [1]. In contrast to the www.impactjournals.com/oncotarget soluble lysosomal hydrolases the knowledge of the protein composition of the lysosomal membrane has remained fragmentary for much longer. This reflects that classical protein purification approaches have been difficult to apply to the analysis of hydrophobic membrane proteins. Over the recent years important insights have been gained from systematic proteomic studies analysing this subcompartment. These have identified several functionally uncharacterized integral membrane proteins with tentative lysosomal residence [2, 6, 7]. One of these candidates was the Transmembrane protein 192, TMEM192, or FLJ38482, according to the previous nomenclature, which was initially reported in lysosomal membranes isolated from human placenta [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
