Two-pore and TRPML cation channels: Regulators of phagocytosis, autophagy and lysosomal exocytosis

The old Greek saying “Panta Rhei” (“everything flows”) is true for all life and all living things in general. It also becomes nicely evident when looking closely into cells. There, material from the extracellular space is taken up by endocytic processes and transported to endosomes where it is sorted either for recycling or degradation. Cargo is also packaged for export through exocytosis involving the Golgi network, lysosomes and other organelles. Everything in this system is in constant motion and many proteins are necessary to coordinate transport along the different intracellular pathways to avoid chaos. Among these proteins are ion channels., in particular TRPML channels (mucolipins) and two-pore channels (TPCs) which reside on endosomal and lysosomal membranes to speed up movement between organelles, e.g. by regulating fusion and fission; they help readjust pH and osmolarity changes due to such processes, or they promote exocytosis of export material. Pathophysiologically, these channels are involved in neurodegenerative, metabolic, retinal and infectious diseases, cancer, pigmentation defects, and immune cell function, and thus have been proposed as novel pharmacological targets, e.g. for the treatment of lysosomal storage disorders, Duchenne muscular dystrophy, or different types of cancer. Here, we discuss the similarities but also differences of TPCs and TRPMLs in regulating phagocytosis, autophagy and lysosomal exocytosis, and we address the contradictions and open questions in the field relating to the roles TPCs and TRPMLs play in these different processes.