Elongation Factor 2 Kinase is regulated by Proline Hydroxylation and protects cells during Hypoxia

Protein synthesis, and especially translation elongation, requires large amounts of energy, which is often generated by oxidative metabolism. Elongation is controlled by phosphorylation of eukaryotic elongation factor 2 (eEF2), which inhibits its activity and is catalysed by eEF2 kinase (eEF2K), a calcium/calmodulin-dependent ?-kinase.Hypoxia causes the activation of eEF2K and induces eEF2 phosphorylation independently of previously-known inputs into eEF2K. Here, we show that eEF2K is subject to hydroxylation on proline-98. Proline hydroxylation is catalysed by proline hydroxylases, oxygen-dependent enzymes which are inactivated during hypoxia. Pharmacological inhibition of proline hydroxylases also stimulates eEF2 phosphorylation. Pro98 lies in a universally-conserved linker between the calmodulin-binding and catalytic domains of eEF2K. Its hydroxylation partially impairs the binding of calmodulin to eEF2K and markedly limits the CaM-stimulated activity of eEF2K. Neuronal cells depend on oxygen and eEF2K helps to protect them from hypoxia.eEF2K is the first example of a protein directly involved in a major energy-consuming process to be regulated by proline hydroxylation. Since eEF2K is cytoprotective during hypoxia and other conditions of nutrient insufficiency, it may be a valuable target for therapy of poorly-vascularised solid tumours

Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy

Eukaryotic elongation factor 2 kinase (eEF2K) inhibits the elongation stage of protein synthesis by phosphorylating its only known substrate, eEF2. eEF2K is tightly regulated by nutrient-sensitive signalling pathways. For example, it is inhibited by signalling through mammalian target of rapamycin complex 1 (mTORC1). It is therefore activated under conditions of nutrient deficiency. Here we show that inhibiting eEF2K or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions, and that this is rescued by compounds that block protein synthesis. This implies that eEF2K protects nutrient-deprived cells by inhibiting protein synthesis. Cells in which signalling through mTORC1 is highly active are very sensitive to nutrient withdrawal. Inhibiting mTORC1 protects them. Our data reveal that eEF2K makes a substantial contribution to the cytoprotective effect of mTORC1 inhibition. eEF2K is also reported to promote another potentially cytoprotective process, autophagy. We have used several approaches to test whether inhibition or loss of eEF2K affects autophagy under a variety of conditions. We find no evidence that eEF2K is involved in the activation of autophagy in the cell types we have studied. We conclude that eEF2K protects cancer cells against nutrient starvation by inhibiting protein synthesis rather than by activating autophagy

Atmospheric Escape and Evolution of Terrestrial Planets and Satellites

International audienceThe origin and evolution of Venus', Earth's, Mars' and Titan's atmospheres are discussed from the time when the active young Sun arrived at the Zero-Age-Main-Sequence. We show that the high EUV flux of the young Sun, depending on the thermospheric composition, the amount of IR-coolers and the mass and size of the planet, could have been responsible that hydrostatic equilibrium was not always maintained and hydrodynamic flow and expansion of the upper atmosphere resulting in adiabatic cooling of the exobase temperature could develop. Furthermore, thermal and various nonthermal atmospheric escape processes influenced the evolution and isotope fractionation of the atmospheres and water inventories of the terrestrial planets and Saturn's large satellite Titan efficiently