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.
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May 2022
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Cover Image
The cover image depicts a BRC repeat:RAD51 complex structure from the protozoan Leishmania infantum. The leishmania BRC1 (green) is superposed with a previously published human BRC4 repeat complex (blue, PDB: 1N0W), revealing novel binding features for the protozoan repeat. Read more in Divergent binding mode for protozoan BRC repeat to RAD51 by Pantelejevs and Hyvönen on pages 1031-1043.
Review Article|
May 23 2022
The role of eIF2 phosphorylation in cell and organismal physiology: new roles for well-known actors
Xuemin Wang;
Xuemin Wang
Lifelong Health, South Australian Health & Medical Research Institute, Adelaide SA5000, Australia
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Christopher G. Proud
Lifelong Health, South Australian Health & Medical Research Institute, Adelaide SA5000, Australia
Correspondence: Christopher G. Proud (christopher.proud@sahmri.com)
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Publisher: Portland Press Ltd
Received:
February 16 2022
Revision Received:
April 21 2022
Accepted:
April 25 2022
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2022
Biochem J (2022) 479 (10): 1059–1082.
Article history
Received:
February 16 2022
Revision Received:
April 21 2022
Accepted:
April 25 2022
Citation
Xuemin Wang, Christopher G. Proud; The role of eIF2 phosphorylation in cell and organismal physiology: new roles for well-known actors. Biochem J 27 May 2022; 479 (10): 1059–1082. doi: https://doi.org/10.1042/BCJ20220068
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