Functional characterization of the lysosomal membrane protein TMEM192 in mice
Autor: | Paul Saftig, Sönke Rudnik, Irm Hermans-Borgmeyer, Markus Glatzel, Thuy Linh Nguyen, Christian Bernreuther, Janna Schneppenheim, Bernd Schröder, Renate Lüllmann-Rauch |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
autophagy Pathology medicine.medical_specialty Glycosylation Endosome Gene Expression Molecular neuroscience Biology Gene Knockout Techniques Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Lysosome medicine Animals Mice Knockout Gene knockdown Autophagy Ubiquitination Brain Membrane Proteins Intracellular Membranes transmembrane protein 192 Fibroblasts Transmembrane protein Cell biology Cytosol 030104 developmental biology medicine.anatomical_structure Liver Oncology Apoptosis proteolytic processing Proteolysis lysosome lysosomal membrane Lysosomes Spleen 030217 neurology & neurosurgery Priority Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | // Thuy Linh Nguyen 1 , Janna Schneppenheim 2 , Sonke Rudnik 1 , Renate Lullmann-Rauch 2 , Christian Bernreuther 3 , Irm Hermans-Borgmeyer 4 , Markus Glatzel 3 , Paul Saftig 1 and Bernd Schroder 1 1 Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany 2 Institute of Anatomy, Christian Albrechts University of Kiel, Kiel, Germany 3 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4 Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Bernd Schroder, email: // Keywords : transmembrane protein 192, lysosome, lysosomal membrane, autophagy, proteolytic processing Received : January 04, 2017 Accepted : April 18, 2017 Published : April 28, 2017 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. |
Databáze: | OpenAIRE |
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