The Lysosome and Intracellular Signalling.

In addition to being the terminal degradative compartment of the cell's endocytic and autophagic pathways, the lysosome is a multifunctional signalling hub integrating the cell's response to nutrient status and growth factor/hormone signalling. The cytosolic surface of the limiting membrane of the lysosome is the site of activation of the multiprotein complex mammalian target of rapamycin complex 1 (mTORC1), which phosphorylates numerous cell growth-related substrates, including transcription factor EB (TFEB). Under conditions in which mTORC1 is inhibited including starvation, TFEB becomes dephosphorylated and translocates to the nucleus where it functions as a master regulator of lysosome biogenesis. The signalling role of lysosomes is not limited to this pathway. They act as an intracellular Ca2+ store, which can release Ca2+ into the cytosol for both local effects on membrane fusion and pleiotropic effects within the cell. The relationship and crosstalk between the lysosomal and endoplasmic reticulum (ER) Ca2+ stores play a role in shaping intracellular Ca2+ signalling. Lysosomes also perform other signalling functions, which are discussed. Current views of the lysosomal compartment recognize its dynamic nature. It includes endolysosomes, autolysosome and storage lysosomes that are constantly engaged in fusion/fission events and lysosome regeneration. How signalling is affected by individual lysosomal organelles being at different stages of these processes and/or at different sites within the cell is poorly understood, but is discussed

The Endosomal Network: Mediators and Regulators of Endosome Maturation

Endocytosis is a means for the cell to sample its environment for nutrients and regulate plasma membrane (PM) composition and area. Whereas the majority of internalized cargo is recycled back to the cell surface, select material is sent to the lysosome for degradation. Endosomes further play major roles in central cell activities as diverse as establishment of cell polarity and signaling, lysosomal storage and immunity. The complexity of endosomal functions is reflected by the extensive changes to endosome properties as they mature. The identity of individual endosomes is influenced by the presence of specific Rab GTPases and phosphoinositides (PIPs), which coordinate membrane traffic and facilitate endosomal functions. Motors and tethers direct the endosomes to the required locations and moderate fusion with other organelles. The maintenance of the elaborate endosomal network is supported by the ER and the trans-Golgi network (TGN), which promote the exchange of membrane components, provide enzymes, and assist with signaling. Additionally, V-ATPase is emerging as an underappreciated coordinator of endosome maturation and cell signaling. The inputs of the various mediators of endosome maturation are tightly regulated and coordinated to ensure appropriate maintenance and functioning of endosomes at each stage of the maturation process. Perturbations in endosome maturation are implicated in devastating diseases, such as neurodegeneration and cancer, and the endosome maturation processes are manipulated and exploited by intracellular pathogens to meet their own needs. A greater understanding of coordination and fine-tuning of endosome maturation will help us address various pathologies more effectively