title: The lysosomal Ca2+release channel TRPML1 regulates lysosome size by activating calmodulin.
abstract: Intracellular lysosomal membrane trafficking, including fusion and fission, is crucial for cellular homeostasis and normal cell function. Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+release. We recently have demonstrated that the lysosomal Ca2+release channel P2X4 regulates lysosome fusion through a calmodulin (CaM)-dependent mechanism. However, the molecular mechanism underlying lysosome fission remains uncertain. In this study, we report that enlarged lysosomes/vacuoles induced by either vacuolin-1 or P2X4 activation are suppressed by up-regulating the lysosomal Ca2+release channel transient receptor potential mucolipin 1 (TRPML1) but not the lysosomal Na+release channel two-pore channel 2 (TPC2). Activation of TRPML1 facilitated the recovery of enlarged lysosomes/vacuoles. Moreover, the effects of TRPML1 on lysosome/vacuole size regulation were eliminated by Ca2+chelation, suggesting a requirement for TRPML1-mediated Ca2+release. We further demonstrate that the prototypical Ca2+sensor CaM is required for the regulation of lysosome/vacuole size by TRPML1, suggesting that TRPML1 may promote lysosome fission by activating CaM. Given that lysosome fission is implicated in both lysosome biogenesis and reformation, our findings suggest that TRPML1 may function as a key lysosomal Ca2+channel controlling both lysosome biogenesis and reformation.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Xi Zoë
authors.initials: XZ
authors.lastname: Zhong
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada. Electronic address: xpdong@dal.ca.
authors.forename: Xian-Ping
authors.initials: XP
authors.lastname: Dong
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; C416674:MCOLN1 protein, human; C530224:TPCN2 protein, human; D050051:Transient Receptor Potential Channels; D002118:Calcium
keywords: calcium; calcium channel; calmodulin (CaM); lysosomal Ca2+; lysosome; membrane trafficking; trpml1