The calcium channel P2X4 stimulates lysosome fusion by activating calmodulin, Cao et al. reveal.
The fusion of lysosomes with each other and with other organelles requires calcium release from the lysosome, but what triggers this release, how calcium crosses the lysosomal membrane, and how it stimulates fusion, remains unknown. Cao et al. focused on the role of lysosomal P2X4, an ATP-activated calcium channel regulated by luminal pH.
Because ATP is always present in the lysosomal lumen, Cao et al. think that luminal pH may be an important regulator of P2X4 activity and lysosome fusion. Overexpressing the channel in cells led to the formation of abnormally large lysosomes. Increasing the pH of the lysosomal lumen also caused enlarged lysosomes and stimulated lysosome fusion. These effects were blocked by knocking down P2X4, inhibiting the channel, or chelating cytoplasmic calcium ions.
The researchers then turned their attention to how calcium induces organelle fusion after its release into the cytosol. Calcium stimulated P2X4’s association with calmodulin, thereby recruiting this calcium-binding protein to lysosomal membranes. Inhibiting calmodulin blocked P2X4’s ability to promote lysosome enlargement, indicating that calmodulin acts downstream of the calcium channel, perhaps by binding to the SNARE proteins that drive lysosome fusion.
Senior author Xian-Ping Dong now wants to investigate how P2X4’s activity is coordinated with the function of another lysosomal calcium release channel, TRPML1, which he believes has a distinct role in promoting lysosome fission.
Text by Ben Short