Regulation of Lysosomal Adaptation to Nutrient Starvation by Lysosomal TRPML1 and PIKfyve

Abstract

Lysosomes play an active role in sensing, signaling, and responding to nutrient availability, in addition to their well-established role in degradation. Lysosomes undergo multifaceted changes in lysosome pH, size, number, and activity, referred to as lysosomal adaptation”, via a transcriptional factor EB (TFEB)-mediated lysosome-to-nucleus signaling pathway. The mechanistic target of rapamycin (mTOR) is a nutrient-sensitive protein kinase that regulates TFEB. When nutrients are abundant, mTOR phosphorylates TFEB on the lysosomal membrane and retains it in the cytosol. When nutrients are deprived, TFEB is dephosphorylated and translocates to the nucleus. Here, I identified two novel components required for lysosomal adaptation: the lysosomal Ca2+ release channel TRPML1 and phosphatidylinositol 3-phosphate (PI3P) 5-kinase PIKfyve. Upon starvation, TRPML1 is activated and PIKfyve is inhibited, both triggering the dephosphorylation and subsequent nuclear translocation of TFEB independent of mTOR. This results in lysosomal changes to enhance degradation capabilities. Moreover, the expression level of TRPML1 is potently and rapidly increased. Pharmacological inhibition or genetic deletion of TRPML1 completely abolishes the effects of starvation on boosting the degradation capability of lysosomes, suggesting that TRPML1 is essential for lysosomal adaptation during prolonged starvation. Collectively, lysosomes may adapt to cellular changes under nutrient deprivation by generating a transcriptional response via TRPML1 activation and PIKfyve inhibition. Modulation of lysosomal function by activating the TRPML1-TFEB pathway may dramatically promote cellular clearance, hence representing a promising therapeutic strategy for many lysosome-related disorders.