GSE136470
Enhanced and selective translation expands the lysosome size and promotes antigen presentation during phagocyte activation
The mechanisms that govern organelle remodeling remain poorly defined. Lysosomes degrade cargo from various routes including endocytosis, phagocytosis and autophagy. For phagocytes, lysosomes are a kingpin organelle since they are essential to kill pathogens and process and present antigens. During phagocyte activation, lysosomes undergo a striking reorganization, changing from dozens of globular structures to a tubular network, in a process that requires the phosphatidylinositol-3-kinase-AKT-mTOR signalling pathway. Here, we show that lysosomes undergo a remarkable expansion in volume and holding capacity during phagocyte activation within 2 h of LPS stimulation. Lysosome expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly independent of TFEB and TFE3 transcription factors, known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTORC1-dependent increase in translation of mRNAs encoding key lysosomal proteins. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for lysosome expansion that relies on mTORC1-dependent enhanced translation of mRNAs to boost protein synthesis and lysosome biogenesis in response to an infection signal. Overall design: Polysome profiling of RAW cells treated with 2h or 6h LPS, LPS in the presence of Torin1, Torin1 or DMSO.