Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation

Significance Two-pore channels (TPCs) are a recently discovered family of endolysosomal ion channels, but their regulation is controversial. By defining the TPC interactome, we provide a community resource that illuminates TPC complex regulation and resolves associations with novel partners and processes. Physical interactions with endolysosomal trafficking regulators predominate, and Rab GTPases impart isoform-specific roles for TPCs in organelle proliferation and cellular pigmentation. These data imply a fundamental role for TPCs in trafficking that augurs significance for disease states exhibiting lysosomal proliferation where TPC dysregulation may drive pathogenesis.