Control of lysosomal biogenesis and Notch-dependent tissue patterning by components of the TFEB-V-ATPase axis in <i>Drosophila melanogaster</i>

<p>In vertebrates, TFEB (transcription factor EB) and MITF (microphthalmia-associated transcription factor) family of basic Helix-Loop-Helix (bHLH) transcription factors regulates both lysosomal function and organ development. However, it is not clear whether these 2 processes are interconnected. Here, we show that Mitf, the single TFEB and MITF ortholog in <i>Drosophila</i>, controls expression of vacuolar-type H⁺-ATPase pump (V-ATPase) subunits. Remarkably, we also find that expression of <i>Vha16-1</i> and <i>Vha13</i>, encoding 2 key components of V-ATPase, is patterned in the wing imaginal disc. In particular, <i>Vha16-1</i> expression follows differentiation of proneural regions of the disc. These regions, which will form sensory organs in the adult, appear to possess a distinctive endolysosomal compartment and Notch (N) localization. Modulation of Mitf activity in the disc in vivo alters endolysosomal function and disrupts proneural patterning. Similar to our findings in <i>Drosophila</i>, in human breast epithelial cells we observe that impairment of the <i>Vha16-1</i> human ortholog <i>ATP6V0C</i> changes the size and function of the endolysosomal compartment and that depletion of TFEB reduces ligand-independent N signaling activity. Our data suggest that lysosomal-associated functions regulated by the TFEB-V-ATPase axis might play a conserved role in shaping cell fate.