Control of
protein synthesis (mRNA translation) plays key roles in shaping the
proteome and in many physiological, including homeostatic, responses. One long-known translational control mechanism involves phosphorylation of
initiation factor,
eIF2, which is catalysed by any one of four
protein kinases, which are generally activated in response to stresses. They form a key arm of the integrated stress response (ISR). Phosphorylated
eIF2 inhibits
eIF2B (the
protein that promotes exchange of
eIF2-bound
GDP for
GTP) and thus impairs general
protein synthesis. However, this mechanism actually promotes translation of certain mRNAs by virtue of specific features they possess. Recent work has uncovered many previously unknown features of this regulatory system. Several studies have yielded crucial insights into the structure and control of
eIF2, including that
eIF2B is regulated by several metabolites. Recent studies also reveal that control of
eIF2 and the ISR helps determine organismal lifespan and surprising roles in sensing mitochondrial stresses and in controlling the
mammalian target of rapamycin (mTOR). The latter effect involves an unexpected role for one of the
eIF2 kinases, HRI. Phosphoproteomic analysis identified new substrates for another
eIF2 kinase, Gcn2, which senses the availability of
amino acids. Several
genetic disorders arise from mutations in genes for eIF2α
kinases or
eIF2B (i.e.
vanishing white matter disease, VWM and
microcephaly, epileptic
seizures,
microcephaly, hypogenitalism, diabetes and
obesity, MEHMO). Furthermore, the eIF2-mediated ISR plays roles in
cognitive decline associated with
Alzheimer's disease. New findings suggest potential therapeutic value in interfering with the ISR in certain settings, including VWM, for example by using compounds that promote
eIF2B activity.