In the present study, we combine genetic and pharmacological manipulations with light and EM to show that inositol triphosphate (IP3)-induced calcium efflux from endoplasmic reticulum (ER) stores in the absence of the IP3-specific inositol polyphosphate-5-phosphatase A (INPP5A) (16, 17), an enzyme downregulated in cancer and defective in spinocerebellar ataxia, triggers lysosome biogenesis via calcineurin-mediated activation of TFEB and TFE3 independent of cellular nutrient status monitored by mTORC1. This evidence concerns the gene INPP5A and cerebellar ataxia.