MTOR‐dependent selective translation rapidly expands lysosome biogenesis, volume and retention capacity during phagocyte activatio

Abstract

The molecular mechanisms that govern and adapt the number, size, morphology and activities of organelles to suit the needs of the many cell types and conditions that these cells may encounter are at the frontier of cell biology. Lysosomes are organelles that degrade cargo from various routes including endocytosis, phagocytosis and autophagy. Lysosomes have also emerged as a signalling platform that senses and integrates stress signals such as nutrient deprivation with regulatory kinase hubs like mTOR and AMPK to modulate metabolic activity. For phagocytes and antigen‐presenting cells like macrophages and dendritic cells, lysosomes are a kingpin organelle since they are essential to kill pathogens, and process and ultimately present antigens. During phagocyte activation with lipopolysaccharides, lysosomes undergo a striking reorganization, changing from dozens of globular objects to a tubular network, in a process that requires the phosphatidylinositol‐3‐kinase‐Akt‐mTOR signalling axis. Ultimately, lysosome tubulation is thought to promote pinocytic retention and antigen presentation. Here, we show that lysosome tubulation is accompanied by a rapid boost in lysosome volume and holding capacity of phagocyte activation. We reveal that lysosome expansion depends on biosynthesis of lysosomal proteins but is independent of TFEB and TFE3, transcription factors known to scale up lysosome biogenesis. Instead, we show that lysosome transcripts are selectively targeted for enhanced protein translation in an mTOR‐dependent manner. Indeed, lysosome transcripts were enriched in polyribosome fractions after lipopolysaccharide exposure in an mTOR‐dependent manner, while transcripts encoding non‐lysosomal proteins were unresponsive to LPS and/or mTOR inhibition. Collectively, we identified an example of rapid organelle expansion and remodelling driven by enhanced and selective protein translation during phagocyte activation.Support or Funding InformationCanadian Institutes of Health Research, Canada Research Chair Program, and Ryerson UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.