The authors observed a growth factor–induced K+ current in patch-clamp recordings of lysosomes extracted from mouse neurons, with features reminiscent of those generated by TMEM175. They then provided several lines of evidence to demonstrate that the described current is mediated by TMEM175 (hence called ITMEM175). Previous work had suggested that lysosomal cation channels may support acidification by conducting K+ out as counter ions for H+ pumped into the lumen (Steinberg, B. E. et al. J. Cell. Biol. https://doi.org/10.1083/jcb.200911083, 2010). Indeed, lysosomes lacking TMEM175 were more alkaline and had defects in lysosome-related cellular functions such as autophagy (Cang, C., Aranda, K., Seo, Y., Gasnier, B. & Ren, D. Cell, https://doi.org/10.1016/j.cell.2015.08.002, 2015). In the present study, these findings are extended to neurons, wherein TMEM175 has protective effects against stress-induced damage.
But how can a lysosomal channel inside the cell respond to growth factor signaling on the outside? The authors found that ITMEM175 crucially depends on AKT, a ubiquitously expressed serine/threonine kinase that is activated by growth factors via phosphoinositide 3-kinase. AKT translates those signals into channel opening by binding a substrate consensus site in a cytosolic loop of TMEM175, close to its central pore. Intriguingly, catalytically-dead AKT was still able to induce ITMEM175, showing that channel activation is independent of AKT’s kinase activity. Instead, pharmacological evidence suggests that activation-induced conformational changes in TMEM175-bound AKT are sufficient to ‘switch on’ TMEM175. Future studies will reveal the mechanistic details of this unexpected activation mechanism coupling lysosomal ion homeostasis to metabolic activity.
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