Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner

• Published in: Journal of molecular cell biology Vol. 6; no. 3; pp. 255 - 266
• Main Authors: Miloslavski, Rachel, Cohen, Elad, Avraham, Adam, Iluz, Yifat, Hayouka, Zvi, Kasir, Judith, Mudhasani, Rajini, Jones, Stephen N, Cybulski, Nadine, Rüegg, Markus A, Larsson, Ola, Gandin, Valentina, Rajakumar, Arjuna, Topisirovic, Ivan, Meyuhas, Oded
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2014
• Subjects: Adaptor Proteins, Signal Transducing; Amino Acids - deficiency; Amino Acids - metabolism; Carrier Proteins - metabolism; Cyclin D3 - metabolism; HEK293 Cells; Humans; Medicin och hälsovetenskap; Monomeric GTP-Binding Proteins - metabolism; mRNA; Oxygen - metabolism; Phosphoproteins - metabolism; Phosphorylation; Protein Biosynthesis; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; RNA 5' Terminal Oligopyrimidine Sequence - genetics; RNA结合蛋白; Signal Transduction; Stress, Physiological; TOP; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - metabolism; 信号通路; 压力条件; 控制; 氧气; 翻译效率; mTOR; hypoxia; translational control; TOP mRNAs; 4E-BP
• ISSN: 1674-2788; 1759-4685; 1759-4685
• DOI: 10.1093/jmcb/mju008

Cells encountering hypoxic stress conserve resources and energy by downregulating the protein synthesis. Here we demonstrate that one mechanism in this response is the translational repression of TOP mRNAs that encode components of the translational apparatus. This mode of regulation involves TSC and Rheb, as knockout of TSC1 or TSC2 or overexpression of Rheb rescued TOP mRNA translation in oxygen-deprived celts. Stress-induced translational repression of these mRNAs closely correlates with the hypophosphorylated state of 4E-BP, a translational repressor. However, a series of 4E-BP loss- and gain-of-function experiments disprove a cause-and- effect relationship between the phosphorylation status of 4E-BP and the translational repression of TOP mRNAs under oxygen or growth factor deprivation. Furthermore, the repressive effect of anoxia is similar to that attained by the very efficient inhibition of mTOR activity by Torin 1, but much more pronounced than roptor or rictor knockouL Likewise, deficiency of raptor or rictor, even though it mildly downregulated basal translation efficiency of TOP mRNAs, failed to suppress the oxygen-mediated translational activation of TOP mRNAs. Finally, co-knockdown of TIA-1 and TIAR, two RNA-binding proteins previously implicated in translational repression of TOP mRNAs in amino acid-starved cells, failed to relieve TOP mRNA translation under other stress conditions. Thus, the nature of the proximal translational regulator of TOP m RNAs remains elusive.