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bioRxiv · 10.1101/277657

mTORC1 controls glycogen synthase kinase 3β nuclear localization and function

Bautista, S. J.·Boras, I.·Vissa, A.·Mecica, N.·Yip, C. M.·Kim, P. K.·Antonescu, C. N.
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Abstract

Glycogen synthase kinase 3{beta} (GSK3{beta}) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3{beta} substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3{beta} function by regulation of its nuclear localization. Inhibition of mechanistic target of rapamycin (mTORC1) led to partial redistribution of GSK3{beta} from the cytosol to the nucleus, and GSK3{beta}-dependent reduction of the expression of c-myc and snail. mTORC1 is controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance. Indeed AMPK activation or amino acid deprivation promoted GSK3{beta} nuclear localization in an mTORC1-dependent manner. GSK3{beta} was detected in several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of Rab7 resulted in loss of GSK3{beta} from lysosomes, and enhanced GSK3{beta} nuclear localization as well as GSK3{beta}-dependent reduction of c-myc levels. This indicates that GSK3{beta} nuclear localization and function is suppressed by mTORC1, and suggests a new link between metabolic conditions sensed by mTORC1 and GSK3{beta}-dependent regulation of transcriptional networks controlling biomass production.\n\nSummary statement (15-30 words)GSK3{beta} nuclear localization and function is negatively regulated by the metabolic and mitogenic sensor mTORC1. mTORC1 control of GSK3{beta} localization requires Rab7 and lysosomal membrane traffic.

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Bautista, S. J., Boras, I., Vissa, A., Mecica, N., Yip, C. M., Kim, P. K., Antonescu, C. N.. 2018-03-06. mTORC1 controls glycogen synthase kinase 3β nuclear localization and function. https://doi.org/10.1101/277657

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