TRPML1 and TFEB, an Intimate Affair

Ca²⁺ is a universal second messenger that plays a wide variety of fundamental roles in cellular physiology. Thus, to warrant selective responses and to allow rapid mobilization upon specific stimuli, Ca²⁺ is accumulated in organelles to keep it at very low levels in the cytoplasm during resting conditions. Major Ca²⁺ storage organelles include the endoplasmic reticulum (ER), the mitochondria, and as recently demonstrated, the lysosome (Xu and Ren, Annu Rev Physiol 77:57-80, 2015). The importance of Ca²⁺ signaling deregulation in human physiology is underscored by its involvement in several human diseases, including lysosomal storage disorders, neurodegenerative disease and cancer (Shen et al., Nat Commun 3:731, 2012; Bae et al., J Neurosci 34:11485-11503, 2014). Recent evidence strongly suggests that lysosomal Ca²⁺ plays a major role in the regulation of lysosomal adaptation to nutrient availability through a lysosomal signaling pathway involving the lysosomal Ca²⁺ channel TRPML1 and the transcription factor TFEB, a master regulator for lysosomal function and autophagy (Sardiello et al., Science 325:473-477, 2009; Settembre et al., Science 332:1429-1433, 2011; Medina et al., Nat Cell Biol 17:288-299, 2015; Di Paola et al., Cell Calcium 69:112-121, 2018). Due to the tight relationship of this lysosomal Ca²⁺ channel and TFEB, in this chapter, we will focus on the role of the TRPML1/TFEB pathway in the regulation of lysosomal function and autophagy.