mTOR Senses Intracellular pH through Lysosome Dispersion from RHEB

• Published in: BioEssays 2019-07, Vol.41 (7), p.e1800265-n/a
• Main Authors: Walton, Zandra E., Brooks, Rebekah C., Dang, Chi V.
• Format: Article
• Language: English
• Subjects: Acidity; Amino acids; Animals; Biosynthesis; Brain; Brain - metabolism; cancer immunity; Cell Hypoxia - physiology; circadian clock; Circadian Clocks - physiology; Circadian rhythms; Deprivation; Dispersion; Homeostasis; Homology; Humans; Hydrogen-Ion Concentration; Hypoxia; Immune response; Immune system; Localization; lysosome trafficking; Lysosomes; Lysosomes - metabolism; mechanistic target of rapamycin (mTOR); Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Mitogens; Neoplasms - pathology; pH effects; Rapamycin; Ras homolog enriched in brain (RHEB); Ras Homolog Enriched in Brain Protein - metabolism; Signal Transduction; Solid tumors; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumors
• ISSN: 0265-9247; 1521-1878; 1521-1878
• DOI: 10.1002/bies.201800265

Acidity, generated in hypoxia or hypermetabolic states, perturbs homeostasis and is a feature of solid tumors. That acid peripherally disperses lysosomes is a three‐decade‐old observation, yet one little understood or appreciated. However, recent work has recognized the inhibitory impact this spatial redistribution has on mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of metabolism. This finding argues for a paradigm shift in localization of mTORC1 activator Ras homolog enriched in brain (RHEB), a conclusion several others have now independently reached. Thus, mTORC1, known to sense amino acids, mitogens, and energy to restrict biosynthesis to times of adequate resources, also senses pH and, via dampened mTOR‐governed synthesis of clock proteins, regulates the circadian clock to achieve concerted responses to metabolic stress. While this may allow cancer to endure metabolic deprivation, immune cell mTOR signaling likewise exhibits pH sensitivity, suggesting that suppression of antitumor immune function by solid tumor acidity may additionally fuel cancers, an obstacle potentially reversible through therapeutic pH manipulation. Multiple studies now indicate that mechanistic target of rapamycin complex 1 (mTORC1) senses intracellular pH. Acid drives lysosome redistribution separating bound mTORC1 from its activator Ras homolog enriched in brain (RHEB). This suggests that RHEB resides on nonlysosomal endomembranes in contrast to prevailing models. Emerging reports regarding RHEB localization are reviewed and strategies to translate mTOR’s pH sensing into cancer immunotherapy are discussed.