Exosome Release Is Regulated by mTORC1

Abstract

Exosomes are small membrane‐bound vesicles released into extracellular spaces by many types of cells. These nanovesicles carry proteins, mRNA, and miRNA, and are involved in cell waste management and intercellular communication. In the present study, it is shown that exosome release, which leads to net loss of cellular membrane and protein content, is negatively regulated by mechanistic target of rapamycin complex 1 (mTORC1). It is found that in cells and animal models exosome release is inhibited by sustained activation of mTORC1, leading to intracellular accumulation of CD63‐positive exosome precursors. Inhibition of mTORC1 by rapamycin or nutrient and growth factor deprivation stimulates exosome release, which occurs concomitantly with autophagy. The drug‐stimulated release is blocked by siRNA‐mediated downregulation of small GTPase Rab27A. Analysis of the cargo content in exosomes released from rapamycin‐treated cells reveals that inhibition of mTORC1 does not significantly alter its majority protein and miRNA profiles. These observations demonstrate that exosome release, like autophagy, is negatively regulated by mTORC1 in response to changes in nutrient and growth factor conditions.

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

“…It was demonstrated that inhibition of mTOR complex 1 (mTORC1; mTOR) by rapamycin or nutrient and growth factor deprivation stimulates exosome release, which occurs concomitantly with autophagy. (32) We also demonstrate that both mTOR and phosphorylation levels of its substrate proteins (S6p70 and 4EBP1) were decreased in alcohol-fed mice. mTOR was shown to be involved in activation of autophagy in hepatocytes after in vitro alcohol treatment.…”

“…A recent study showed a role of mTOR in the regulation of exosome release. It was demonstrated that inhibition of mTOR complex 1 (mTORC1; mTOR) by rapamycin or nutrient and growth factor deprivation stimulates exosome release, which occurs concomitantly with autophagy . We also demonstrate that both mTOR and phosphorylation levels of its substrate proteins (S6p70 and 4EBP1) were decreased in alcohol‐fed mice.…”

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

“…Sustained activation of mTORC1 reduces the release of exosomes by cells and in animal models, resulting in the intracellular accumulation of ILVs. Conversely, exosome release is stimulated by inhibition of mTORC1 by rapamycin or nutrient and growth factor deprivation (Zou et al, 2019). Inhibition of autophagy by wortmannin or CRISPR/Cas9-mediated knockout of the autophagy protein Atg5 (autophagy-related 5) in neuronal cell lines increased the release of exosomes, documenting this interrelationship in neurons as well as other cell types (Dias et al, 2016).…”

Exosomes in osteoarthritis and cartilage injury: advanced development and potential therapeutic strategies

“…The biogenesis and release of exosomes is a complex symphony involving a series of factors, representatively including the endosomal sorting complexes required for transport (ESCRT), ALIX (also known as programed cell death 6-interacting protein, PDCD6IP), phospholipase, vacuolar protein sorting-associated 4 (VPS4), Rab GTPase proteins, sphingomyelinase and ceramide. Recently, the inhibition effect of exosome release was reported by sustained activation of mechanistic target of rapamycin complex 1 (mTORC1) in both cells and animal models, while inhibition of mTORC1 stimulated the release of exosomes, which occurred concomitantly with autophagy [9] .…”