Control of lysosomal biogenesis and Notch-dependent tissue patterning by components of the TFEB-V-ATPase axis inDrosophila melanogaster

Abstract

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 Drosophila, controls expression of vacuolar-type H+-ATPase pump (V-ATPase) subunits. Remarkably, we also find that expression of Vha16-1 and Vha13, encoding 2 key components of V-ATPase, is patterned in the wing imaginal disc. In particular, Vha16-1 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 Drosophila, in human breast epithelial cells we observe that impairment of the Vha16-1 human ortholog ATP6V0C 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.

The Function of V-ATPases in Cancer

“…This cleavage defect upon V-ATPase inhibition could be due to the dependence of ␥-secretase on an acidic environment to cleave the Notch receptor, or it could be that the acidic pH generated by the V-ATPase serves to activate cofactors that stimulate cleavage. Similar effects were also observed in normal and transformed human cell lines, as well as during mouse development (86,92,178,198). In Notch-addicted breast tumor cell lines, V-ATPase inhibition reduced cell proliferation (86).…”

“…Correct processing and trafficking of the Notch receptor requires V-ATPase function (40, 86,155,178,206,207,223). Notch receptor expression is also impaired by prolonged V-ATPase inhibition (198). The first evidence for the involvement of the V-ATPase in Notch signaling came from studies in Drosophila, which demonstrated that mutations in V-ATPase genes or in Rabconnectin-3A and 3B, both regulators of V-ATPase function, diminished Notch signaling and altered receptor trafficking (206,223).…”

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

“…Metabolic signals such as mTORC1 inhibition drive dephosphorylation and nuclear translocation of TFEB, thus promoting the activation of genes involved in lysosomal function and autophagy (14,53). PPAR-a agonists enhance the transcriptional activation of TFEB via direct binding to and regulation of its promoter regions in brain cells and fly models (54,55). In addition, TFEB was activated in murine macrophages by Staphylococcus aureus infection and contributed to transcriptional induction of inflammatory cytokines and chemokines (56).…”

TFEB at a glance

“…A functional lysosomal compartment is also required for Notch activation (Vaccari et al, 2010). Accordingly, depletion of Drosophila MITF results in impaired Notch signaling and developmental defects (Tognon et al, 2016). Thus MiT proteins, by controlling lysosomal homeostasis, ensure proper activation of key signaling pathways that orchestrate developmental and differentiation processes.…”

“…Finally, work in D. melanogaster has shown that the TFEB orthologue Mitf has an important role in the modulation of lysosomal genes, especially the subunits of the v-ATPase proton pump, as well as in the induction of intracellular clearance and reduction of protein aggregates, and in organ development (Bouche et al, 2016;Tognon et al, 2016;Zhang et al, 2015).…”