Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 36, Pages 13087-13092Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1407004111
Keywords
Ca2+ signaling; lysosome; Xenopus
Categories
Funding
- National Institutes of Health [GM088790, DA035926, DA023204]
- Biotechnology and Biological Sciences Research Council [BB/G013721/1]
- Bogue Research Fellowship
- BBSRC [BB/G013721/1, BB/K000942/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G013721/1, BB/K000942/1] Funding Source: researchfish
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The two-pore channels (TPC1 and TPC2) belong to an ancient family of intracellular ion channels expressed in the endolysosomal system. Little is known about how regulatory inputs converge to modulate TPC activity, and proposed activation mechanisms are controversial. Here, we compiled a proteomic characterization of the human TPC interactome, which revealed that TPCs complex with many proteins involved in Ca2+ homeostasis, trafficking, and membrane organization. Among these interactors, TPCs were resolved to scaffold Rab GTPases and regulate endomembrane dynamics in an isoform-specific manner. TPC2, but not TPC1, caused a proliferation of endolysosomal structures, dysregulating intracellular trafficking, and cellular pigmentation. These outcomes required both TPC2 and Rab activity, as well as their interactivity, because TPC2 mutants that were inactive, or rerouted away from their endogenous expression locale, or deficient in Rab binding, failed to replicate these outcomes. Nicotinic acid adenine dinucleotide phosphate (NAADP)evoked Ca2+ release was also impaired using either a Rab binding-defective TPC2 mutant or a Rab inhibitor. These data suggest a fundamental role for the ancient TPC complex in trafficking that holds relevance for lysosomal proliferative scenarios observed in disease.
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