Lopinavir impairs protein synthesis and induces eEF2 phosphorylation via the activation of AMP-activated protein kinase.

Journal of Cellular Biochemistry
Ly Q Hong-BrownCharles H Lang

Abstract

HIV anti-retroviral drugs decrease protein synthesis, although the underlying regulatory mechanisms of this process are not fully established. Therefore, we investigated the effects of the HIV protease inhibitor lopinavir (LPV) on protein metabolism. We also characterized the mechanisms that mediate the effects of this drug on elongation factor-2 (eEF2), a key component of the translational machinery. Treatment of C2C12 myocytes with LPV produced a dose-dependent inhibitory effect on protein synthesis. This effect was observed at 15 min and was maintained for at least 4 h. Mechanistically, LPV increased the phosphorylation of eEF2 and thereby decreased the activity of this protein. Increased phosphorylation of eEF2 was associated with increased activity of its upstream regulators AMP-activated protein kinase (AMPK) and eEF2 kinase (eEF2K). Both AMPK and eEF2K directly phosphorylated eEF2 in an in vitro kinase assay suggesting two distinct paths lead to eEF2 phosphorylation. To verify this connection, myocytes were treated with the AMPK inhibitor compound C. Compound C blocked eEF2K and eEF2 phosphorylation, demonstrating that LPV affects eEF2 activity via an AMPK-eEF2K dependent pathway. In contrast, incubation of myocytes with...Continue Reading

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Citations

Jul 24, 2018·Proteomics. Clinical Applications·Niannian WangKeping Chen
Mar 11, 2015·Molecular and Cellular Biology·Claire E J MooreChristopher G Proud
Jul 7, 2016·American Journal of Physiology. Endocrinology and Metabolism·John O OgunbilejeLabros S Sidossis
Feb 9, 2017·Nature Reviews. Urology·Ayesha S Khan, Daniel E Frigo
Mar 12, 2015·American Journal of Physiology. Endocrinology and Metabolism·Jennifer L Steiner, Charles H Lang
Jan 16, 2021·International Journal of Molecular Sciences·Camille FraichardJean Guibourdenche

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