Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion |
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Authors: | Qi Cao Xi Zo? Zhong Yuanjie Zou Ruth Murrell-Lagnado Michael X. Zhu Xian-Ping Dong |
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Affiliation: | 1Department of Physiology and Biophysics, Dalhousie University, Halifax B3H 4R2, Nova Scotia, Canada;2Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, England, UK;3Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030 |
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Abstract: | Intra-endolysosomal Ca2+ release is required for endolysosomal membrane fusion with intracellular organelles. However, the molecular mechanisms for intra-endolysosomal Ca2+ release and the downstream Ca2+ targets involved in the fusion remain elusive. Previously, we demonstrated that endolysosomal P2X4 forms channels activated by luminal adenosine triphosphate in a pH-dependent manner. In this paper, we show that overexpression of P2X4, as well as increasing endolysosomal P2X4 activity by alkalinization of endolysosome lumen, promoted vacuole enlargement in cells and endolysosome fusion in a cell-free assay. These effects were prevented by inhibiting P2X4, expressing a dominant-negative P2X4 mutant, and disrupting the P2X4 gene. We further show that P2X4 and calmodulin (CaM) form a complex at endolysosomal membrane where P2X4 activation recruits CaM to promote fusion and vacuolation in a Ca2+-dependent fashion. Moreover, P2X4 activation-triggered fusion and vacuolation were suppressed by inhibiting CaM. Our data thus suggest a new molecular mechanism for endolysosomal membrane fusion involving P2X4-mediated endolysosomal Ca2+ release and subsequent CaM activation. |
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