Lysosomes are the major cellular site for clearance of defective organelles and digestion of internalized material. Demand on lysosomal capacity varies greatly, but the mechanisms that adjust lysosomal function to maintain cellular homeostasis are unknown. In this study, we identify an interaction between mTOR and the TFEB transcription factor on the surface of lysosomes that allows mTOR to transduce signals arising from changes in lysosomal status to TFEB and thus control the ability of TFEB to enter the nucleus. This occurs via regulation of the serine 211 phosphorylation-dependent binding of 14-3-3 proteins to TFEB. These results identify TFEB as a novel target of mTOR that couples the transcriptional regulation of genes encoding proteins of autophagosomes and lysosomes to cellular need. We further present evidence that the closely related MITF and TFE3 transcription factors are regulated in a similar manner, thus broadening the range of physiological contexts under which such regulation may prove important.

Dynamin, the founding member of a family of dynamin-like GTPases (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live cell imaging, cell free-studies, X-ray crystallography and genetic studies in mice has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged that highlight specific contributions of this GTPase to the physiology of different tissues.

Dynamin 1 is a neuron-specific guanosine triphosphatase thought to be critically required for the fission reaction of synaptic vesicle endocytosis. Unexpectedly, mice lacking dynamin 1 were able to form functional synapses, even though their postnatal viability was limited. However, during spontaneous network activity, branched, tubular plasma membrane invaginations accumulated, capped by clathrin-coated pits, in synapses of dynamin 1-knockout mice. Synaptic vesicle endocytosis was severely impaired during strong exogenous stimulation but resumed efficiently when the stimulus was terminated. Thus, dynamin 1-independent mechanisms can support limited synaptic vesicle endocytosis, but dynamin 1 is needed during high levels of neuronal activity.