Editors' ChoiceStem Cells

Linking lysosomes to stem cell differentiation

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Sci. Signal.  26 Feb 2019:
Vol. 12, Issue 570, eaax0926
DOI: 10.1126/scisignal.aax0926

Lysosomal signaling enables stem cell differentiation by sequestering the transcription factor Tfe3 in the cytoplasm.

Cellular metabolism and signaling through the nutrient sensor mechanistic target of rapamycin complex 1 (mTORC1) are implicated in the differentiation of embryonic stem cells (ESCs). Under nutrient-rich conditions, the lysosomal Ragulator complex recruits heterodimeric Rag GTPases, which are composed of either an A or B (A/B) subunit together with a C or D (C/D) subunit. The Rag GTPase in turn recruits mTORC1, leading to mTORC1 activation. In addition to suppressing autophagy and stimulating protein biosynthesis, mTORC1 phosphorylates the transcription factor Tfe3, thus preventing Tfe3 from entering the nucleus to activate genes involved in lysosome biogenesis. Villegas et al. found that RagC, the RagC/D GTPase-activating protein (GAP) Folliculin (Flcn), and components of the Ragulator complex were required for the spontaneous differentiation of mouse ESCs. Ragulator and Flcn mediated the recruitment of RagC, RagD, and Tfe3 to the lysosomal membrane, thus sequestering Tfe3 in the cytoplasm. In contrast, neither mTORC1 activation nor the RagA/B GAP GATOR1 was required for the cytoplasmic sequestration of Tfe3 in ESCs, implying that Tfe3 sequestration can be controlled by both mTORC1-dependent and -independent mechanisms and that RagA/B is required for the nutrient-induced activation of mTORC1 but not for the differentiation of nonstarved ESCs. Pharmacological inhibition of lysosomal catabolism or mutations in Tfe3 that prevented its recruitment to lysosomes prevented cytoplasmic sequestration of Tfe3, thus enabling it to enter the nucleus and block differentiation. The authors identified mutations in TFE3 that are associated with hypomelanosis of Ito, a developmental disorder that affects the musculoskeletal and nervous systems, as well as the skin. Corresponding mutations in mouse Tfe3 prevented spontaneous differentiation of ESCs into neural progenitors. These findings provide a mechanistic link between lysosomal activity and stem cell differentiation, but further studies are needed to elucidate the integration of mTORC1-dependent and -independent signaling at lysosomal membranes and the contributions of distinct Rag GTPase subunits (see commentary by Roczniak-Ferguson and Ferguson).

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