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

Journal of Molecular Cell Biology 2014年第3期8卷 255-266页

作者： Rachel Miloslavski Elad Cohen Adam Avraham Yifat I luz Zvi Hayouka Judith Kasir rajini mudhasani Stephen N. Jones Nadine Cybulski Markus A. Ruegg Ola Larsson Valentina Gandin Arjuna Rajakumar Ivan Topisirovic Oded Meyuhas Department of Biochemistry and Molecular Biology The Institute for Medical Research - Israel-Canada The Hebrew University-Hadassah Medical School Jerusalem 91120 Israel Department of Cell Biology University of Massachusetts Medical School North Worcester MA 01655 USA Biozentrum University of Basel Klingelbergstrasse 70 CH-4056 Basel Switzerland Department of Oncolo'gy-Pathology Karolinska Instituie Stockholm SE-171 76 Sweden Lady Davis Institute for Medical Research Sir Mortimer B. Davis-Jewish General Hospital and Department of Oncology McGill University Montreal QC H3T 1E2 Canada Present address: Migal-Galilee Research Institute Kiryat Shmona 11016 Israel Present address: United States Army Medical Research Institute of Infectious Diseases Frederick MD 21702-5011 USA Present address: ADAM Montreal QC H3N 2C7 Canada

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.

关键词： hypoxia roTOR TOP mRNAs translational control 4E-BP

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