A Retrospective on eIF2A—and Not the Alpha Subunit of eIF2

Komar, Anton A.; Merrick, William C.

doi:10.3390/ijms21062054

Cited by 51 publications

(56 citation statements)

References 139 publications

(410 reference statements)

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“…We note that in most cases eIF2α phosphorylation is known to acutely suppress translation 74 , yet we observed a net increase of protein synthesis in CKO cells (Figure 3C, S4D-E). This may be reconciled by our observation that density regulated protein (DENR) and eIF2A, additional alternative subunits of the translation initiation complex, were significantly upregulated in CKO cells compared with WT (Figure S6B-C); and suggests a mechanism whereby chronically stressed CKO cells may overcome increased basal eIF2α phosphorylation, that normally only occurs under acute stress 78–81 .…”

Section: Resultsmentioning

confidence: 87%

CRYPTOCHROME suppresses the circadian proteome and promotes protein homeostasis

Wong

Seinkmane

Stangherlin

et al. 2020

Preprint

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13Circadian timekeeping in mammalian cells involves daily cycles of CRYPTOCHROME-dependent 14 transcriptional feedback repression. Ablation of CRY in mice leads to reduced growth and numerous 15 other phenotypes for reasons that are not well understood. Here, we find that cells adapt to CRY 16 deficiency by extensive remodelling of the proteome, phosphoproteome and ionome, with twice the 17 number of circadian-regulated proteins and phosphopeptides as well as increased rhythmic ion 18 transport compared to wild-type cells. CRY-deficient cells also have increased protein synthesis and 19 reduced proteasomal degradation, as well as an altered energetic state. These adaptations render cells 20 more sensitive to stress, and may provide an explanation for the wide-ranging phenotypes of CRY-21 deficient mice. We suggest that daily rhythms in cellular protein abundance are damped by CRY-22 mediated repression to facilitate daily cycles of proteome renewal whilst maintaining protein 23 homeostasis. 24 25 complex containing the activating transcription factors (BMAL1 and CLOCK or NPAS2). The 52 stability, interactions and nucleocytoplasmic shuttling of the encoded PER and CRY proteins is 53 regulated post-translationally until, many hours later, they repress the activity of BMAL1-containing 54 complexes. This transcriptional-translational feedback loop (TTFL) is proposed as the basis of 55 circadian timekeeping in mammalian cells [15]. Genes whose transcription are regulated by core 56 TTFL factors are thought to drive circadian rhythms in the encoded proteins to control myriad cellular 57 functions [13,14]. 58 59 Within the TTFL model of circadian rhythm generation, CRY proteins are the essential repressors of 60 CLOCK/BMAL1 activity [16,17], and have long been considered indispensable for circadian 61 rhythms in vivo and cells ex vivo [18][19][20][21][22]. In contrast, PER proteins play critical signalling and 62 scaffolding roles, required for the nuclear import and targeting of CRY to BMAL1-containing 63 complexes [17]. Recently however, we found that CRY-deficient cells, tissues and mice retain the 64 capacity for circadian timing, in the absence of canonical TTFL function [23]. Similarly, circadian 65 oscillations were retained in cells and tissue slices lacking BMAL1 [24]. Whilst we cannot exclude 66 the presence of some unknown transcriptional feedback-driven oscillation, many previous 67 observations argue against this [12,17,19,21,22,[25][26][27][28]. Recent evidence supports the hypothesis that 68 a conserved post-translational cytosolic oscillator (PTO, or "cytoscillator") may be responsible for 69 generating the oscillation from which circadian transcriptional cycles derive [12,29,30]. Thus, while 70 the TTFL is crucial for rhythmic robustness and co-ordinating outputs, it is not required for generation 71 of rhythms. 72 73The complex phenotype of mice lacking CRY proteins has been interpreted to mean that circadian 74 timekeeping is crucial for organismal physiology. The emerging observations that circadia...

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Section: Resultsmentioning

confidence: 87%

CRYPTOCHROME suppresses the circadian proteome and promotes protein homeostasis

Wong

Seinkmane

Stangherlin

et al. 2020

Preprint

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“…Amino acid starvation and deacylated tRNAs are known to induce ISR by activating the eIF2a kinase GCN2 ( 36 ). Recently, ribosome stalling was reported as an an alternative mechanism that can activate ISR via the CGN2-mediated phosphorylation of eIF2a ( 15 , 37 ).…”

Section: Resultsmentioning

confidence: 99%

Charcot–Marie–Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response

Mendonsa

Kuegelgen

Bujanic

et al. 2021

Nucleic Acids Research

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Toxic gain-of-function mutations in aminoacyl-tRNA synthetases cause a degeneration of peripheral motor and sensory axons, known as Charcot–Marie–Tooth (CMT) disease. While these mutations do not disrupt overall aminoacylation activity, they interfere with translation via an unknown mechanism. Here, we dissect the mechanism of function of CMT mutant glycyl-tRNA synthetase (CMT-GARS), using high-resolution ribosome profiling and reporter assays. We find that CMT-GARS mutants deplete the pool of glycyl-tRNAGly available for translation and inhibit the first stage of elongation, the accommodation of glycyl-tRNA into the ribosomal A-site, which causes ribosomes to pause at glycine codons. Moreover, ribosome pausing activates a secondary repression mechanism at the level of translation initiation, by inducing the phosphorylation of the alpha subunit of eIF2 and the integrated stress response. Thus, CMT-GARS mutant triggers translational repression via two interconnected mechanisms, affecting both elongation and initiation of translation.

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“…Protein expression and protein degradation are tightly controlled processes. An important regulator of protein translation is the factor eIF2α [ 9 – 12 ]. Phosphorylation of eIF2α S51 inactivates its function, and bulk protein translation is reduced.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43

Dent

Booth

Roberts

et al. 2021

Aging

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Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer’s Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.

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A Retrospective on eIF2A—and Not the Alpha Subunit of eIF2

Cited by 51 publications

References 139 publications

CRYPTOCHROME suppresses the circadian proteome and promotes protein homeostasis

CRYPTOCHROME suppresses the circadian proteome and promotes protein homeostasis

Charcot–Marie–Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43

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