Glutamine-dependent lysosome homeostatic changes induced by starvation and lysosome inhibition

• Published in: Biochimica et biophysica acta. Molecular cell research 2018-09, Vol.1865 (9), p.1356-1367
• Main Authors: Wilden, Alexa R., Molina, Joshua A., Feuerborn, Melissa, Boyle, Daniel, Lee, Stella Y.
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Cell Line; Glutamine; Glutamine - drug effects; HeLa Cells; Homeostasis; Humans; Lysosomes; Lysosomes - physiology; Mice; mTOR; TFEB; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2018.06.014

Lysosomes are a major organelle for degrading macromolecules. When deprived of nutrients, cells activate the autophagy and lysosome biogenesis pathways to recycle cytoplasmic materials and to increase lysosomal degradation capacity for survival, respectively. We have identified a condition in which cells accumulated enlarged lysosomes upon starvation and lysosome inhibition. Selective autophagy and inhibition of the mechanistic target of rapamycin (mTOR) in combination with lysosome inhibition were not able to induce this phenomenon. Conversely, knocking out autophagy genes, ATG5 or ATG7, had no effects on the enlarged lysosome formation. This suggests that the enlarged lysosome formation is an autophagy independent process. Remarkably, adding glutamine to the treatment can prevent formation of the enlarged lysosomes and dissipate the pre-existing ones. Furthermore, the nucleus/cytoplasm translocation of the transcription factor EB (TFEB), but not mTOR activity, correlates with the formation/dissipation of enlarged lysosomes. Knockdown of TFEB, however, suggests that TFEB-mediated lysosome biogenesis is not directly involved in the process. These results indicate that there is a novel mechanism by which lysosome homeostasis can be regulated under certain stress conditions. •Starvation with lysosome inhibition induces enlarged lysosome formation.•The formation of enlarged lysosomes is autophagy and mTOR independent.•The addition of glutamine prevents the enlarged lysosome formation.•The addition of glutamine dissipates the pre-existing enlarged lysosomes.•TFEB translocation correlates with formation/dissipation of enlarged lysosomes.