Format

Send to

Choose Destination
Sci Rep. 2017 Aug 30;7(1):10038. doi: 10.1038/s41598-017-10607-4.

The two-pore channel TPC1 is required for efficient protein processing through early and recycling endosomes.

Author information

1
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, Albert-Ludwigs-University, Albertstrasse 25, 79104, Freiburg, Germany.
2
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-University, Munich, Germany.
3
Institute of Physiology II, Faculty of Medicine, Albert-Ludwigs-University, Hermann-Herder-Strasse 7, 79104, Freiburg, Germany.
4
Logopharm GmbH, Schlossstrasse 14, 79232, March-Buchheim, Germany.
5
Center for Biological Signaling Studies (BIOSS), Schänzlestrasse 18, 79104, Freiburg, Germany.
6
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, Albert-Ludwigs-University, Albertstrasse 25, 79104, Freiburg, Germany. n.klugbauer@pharmakol.uni-freiburg.de.

Abstract

Two-pore channels (TPCs) are localized in endo-lysosomal compartments and assumed to play an important role for vesicular fusion and endosomal trafficking. Recently, it has been shown that both TPC1 and 2 were required for host cell entry and pathogenicity of Ebola viruses. Here, we investigate the cellular function of TPC1 using protein toxins as model substrates for distinct endosomal processing routes. Toxin uptake and activation through early endosomes but not processing through other compartments were reduced in TPC1 knockout cells. Detailed co-localization studies with subcellular markers confirmed predominant localization of TPC1 to early and recycling endosomes. Proteomic analysis of native TPC1 channels finally identified direct interaction with a distinct set of syntaxins involved in fusion of intracellular vesicles. Together, our results demonstrate a general role of TPC1 for uptake and processing of proteins in early and recycling endosomes, likely by providing high local Ca2+ concentrations required for SNARE-mediated vesicle fusion.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center