Rapsyn is a scaffold protein with a well-established role in the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction. However, although rapsyn is also expressed in non-muscle cells and undifferentiated myoblasts, its subcellular localisation and function in these cells are completely unknown. On page in this issue, Mohammed Akaaboune and colleagues discover a novel role for rapsyn in COS7 cells and undifferentiated myoblasts, which do not express AChRs. They showed that rapsyn colocalised with the lysosome marker Lamp1, particularly at vacuolar junctions. However, ectopic expression of AChRs resulted in relocalisation of rapsyn to the plasma membrane, suggesting that rapsyn might only have a role at the lysosome in cells that do not have AChRs. By quantifying the spread and velocity of lysosomes, the authors observed that overexpression of rapsyn caused lysosomes to cluster in a juxtanuclear region. Furthermore, in myoblasts isolated from rapsyn-knockout mice, lysosomes were more scattered and moved with higher velocity than those in myoblasts from control mice. Interestingly, the myrystoylation site, the coiled-coil and RING H2 domains were all necessary for rapsyn to localise to lysosomes and to induce their clustering, as well as for the rescue of scattered lysosomes in rapsyn-knockout cells. Finally, the authors found that cells lacking rapsyn showed increased lysosome exocytosis and higher susceptibility to plasma membrane damage, indicating that, owing to its role in lysosomal positioning, rapsyn might indirectly regulate plasma membrane homeostasis.
