Lysosomes respond to environmental cues by controlling their own biogenesis, but the underlying mechanisms are poorly understood. Here we describe a protein kinase C (PKC)-dependent and mTORC1-independent mechanism for regulating lysosome biogenesis, which provides insights into previously reported effects of PKC on lysosomes. By identifying lysosome-inducing compounds we show that PKC couples activation of the TFEB transcription factor with inactivation of the ZKSCAN3 transcriptional repressor through two parallel signalling cascades. Activated PKC inactivates GSK3β, leading to reduced phosphorylation, nuclear translocation and activation of TFEB, while PKC activates JNK and p38 MAPK, which phosphorylate ZKSCAN3, leading to its inactivation by translocation out of the nucleus. PKC activation may therefore mediate lysosomal adaptation to many extracellular cues. PKC activators facilitate clearance of aggregated proteins and lipid droplets in cell models and ameliorate amyloid β plaque formation in APP/PS1 mouse brains. Thus, PKC activators are viable treatment options for lysosome-related disorders.

In the neurogenic niches, adult neural stem and/or progenitor cells (NSCs) generate functional neurons throughout life, which has been implicated in learning and memory and affective behaviors. During adult neurogenesis, newborn neurons release feedback signals into the niches to regulate NSC proliferation and differentiation. However, whether and how NSCs contribute to the niche governing newborn neuron development is still unknown. Using a combination of cell ablation, retrovirus-mediated single-cell labeling, and signaling pathway modulation, we show that adult hippocampal NSCs continuously supply pleiotrophin factor to the newborn neurons. Without this feedforward signal, the newborn neurons display defective dendritic development and arborization. Thus, our findings reveal that NSCs behave as a functional niche for newly generated newborn neurons to regulate their maturation.