Alcohol and PRAS40 knockdown decrease mTOR activity and protein synthesis via AMPK signaling and changes in mTORC1 interaction.

Journal of Cellular Biochemistry
Ly Q Hong-BrownCharles H Lang

Abstract

The mTORC1 protein kinase complex consists of mTOR, raptor, mLST8/GbetaL and PRAS40. Previously, we reported that mTOR plays an important role in regulating protein synthesis in response to alcohol (EtOH). However, the mechanisms by which EtOH regulates mTORC1 activity have not been established. Here, we investigated the effect of EtOH on the phosphorylation and interaction of components of mTORC1 in C2C12 myocytes. We also examined the specific role that PRAS40 plays in this process. Incubation of myocytes with EtOH (100 mM, 24 h) increased raptor and PRAS40 phosphorylation. Likewise, there were increased levels of the PRAS40 upstream regulators Akt and IRS-1. EtOH also caused changes in mTORC1 protein-protein interactions. EtOH enhanced the binding of raptor and PRAS40 with mTOR. These alterations occurred in concert with increased binding of 14-3-3 to raptor, while the PRAS40 and 14-3-3 interaction was not affected. The shRNA knockdown (KD) of PRAS40 decreased protein synthesis similarly to EtOH. PRAS40 KD increased raptor phosphorylation and its association with 14-3-3, whereas decreased GbetaL-mTOR binding. The effects of EtOH and PRAS40 KD were mediated by AMPK. Both factors increased in vitro AMPK activity towards the su...Continue Reading

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Citations

Oct 20, 2012·Alcohol and Alcoholism : International Journal of the Medical Council on Alcoholism·Anne M PruznakCharles H Lang
Mar 24, 2012·American Journal of Physiology. Cell Physiology·Ly Q Hong-BrownCharles H Lang
Dec 24, 2011·American Journal of Physiology. Gastrointestinal and Liver Physiology·Suthat LiangpunsakulDavid W Crabb
Mar 29, 2011·Alcoholism, Clinical and Experimental Research·Ly Q Hong-BrownCharles H Lang
Jul 31, 2013·Alcoholism, Clinical and Experimental Research·Ly Q Hong-BrownCharles H Lang
Mar 24, 2011·Hepatology Research : the Official Journal of the Japan Society of Hepatology·Suzanne M de la MonteJack R Wands
Apr 29, 2016·Alcoholism, Clinical and Experimental Research·Johann K Eberhart, Scott E Parnell
Jan 10, 2017·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Adrian TaylorMarica Bakovic
Mar 17, 2017·Alcoholism, Clinical and Experimental Research·Ly Q Hong-BrownCharles H Lang
Jan 29, 2021·Journal of Drug Targeting·Qun ZhouLinxi Chen
Sep 29, 2021·Alcoholism, Clinical and Experimental Research·Eric W FishScott E Parnell

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