Endoplasmic reticulum proteostasis impairment in aging

Martínez, Gabriela; Duran‐Aniotz, Claudia; Cabral‐Miranda, Felipe; Vivar, Juan P.; Hetz, Claudio

doi:10.1111/acel.12599

Cited by 172 publications

(129 citation statements)

References 123 publications

(146 reference statements)

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“…This remarkable effect relies on translation-dependent remodeling of neuronal synapses (20). eIF2 phosphorylation correlates with diverse neurodegenerative diseases and cancers, as well as normal aging (21)(22)(23)(24). Additionally, a number of mutations that impair eIF2B activity lead to a neurodegenerative disorder of childhood known as vanishing white matter disease (VWMD) that is marked by cerebellar ataxia, spasticity, hypersensitivity to head trauma and infection, coma and premature death (25).…”

Section: Main Textmentioning

confidence: 99%

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule

Tsai

Miller-Vedam

Anand

et al. 2017

Preprint

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Abstract:Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from substrate to competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation and, remarkably, in rodents enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by electron cryomicroscopy. Structural and biochemical analyses revealed that formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and that ISRIB promoted this step by cross-bridging a central symmetry interface. Regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/222257 doi: bioRxiv preprint first posted online Nov. 22, 2017; Main Text:Protein quality control is essential to the maintenance of cellular and organismal health. To prevent the production of deleterious proteins, such as those from invading viruses or those produced in misfolding-prone environments, cells regulate protein synthesis. By arresting or accelerating the cardinal decision of translation initiation, cells effect proteome-wide changes that drive organismal functions, such as development, memory, and immunity (1-3).A key enzyme in the regulation of protein synthesis is eukaryotic translation initiation factor 2B (eIF2B), a dedicated guanine nucleotide exchange factor (GEF) for translation initiation factor 2 (eIF2). eIF2B is composed of five subunits (α,β,γ,δ,ε) that assemble into a decamer composed of two copies of each subunit (4-8). The eIF2Bε subunit contains the enzyme's catalytic center and associates closely with eIF2Bγ (9). Two copies each of the structurally homologous eIF2Bα, β, and δ subunits form the regulatory core that modulates eIF2B's catalytic activity (10-12).eIF2B's substrate, eIF2 is composed of three subunits (α,β,γ) and binds methionine initiator tRNA and GTP to form the ternary complex required to initiate translation on AUG start codons. eIF2's γ subunit contains the GTP-binding pocket (as reviewed in (13, 14)).In response to various inputs, many of which are cell stresses, phosphorylation of eIF2α at serine 51 converts eIF2 from a substrate for nucleotide exchange to a competitive inhibitor of eIF2B.Phosphorylated eIF2 binds to eIF2B with enhanced affinity, effectively sequestering the limiting eIF2B complex from engaging unphosphorylated eIF2 for nucleotide exchange (10-12). Such inhibition leads to an attenuation of general translation and, paradox...

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Section: Main Textmentioning

confidence: 99%

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule

Tsai

Miller-Vedam

Anand

et al. 2017

Preprint

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“…Accumulation of intracellular aggregates composed by misfolded proteins during aging deteriorates cellular function. 24) Consistently, we previously found that muscular taurine depletion activates unfolded protein response (UPR) signal pathway, 22) which may be resulted from impairment of protein homeostasis by taurine loss. Therefore, we tested whether endoplasmic reticulum (ER) stress is associated with an induction in GDF15.…”

Section: Induction In Gdf15 In Aged Tautko Musclementioning

confidence: 73%

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse

Ito

Nakanishi

Yamaji

et al. 2018

Biological & Pharmaceutical Bulletin

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It has been identified that skeletal muscle is an endocrine tissue. Since skeletal muscle aging affects not only to muscle strength and function but to systemic aging and lifespan, myokines secreted from skeletal muscle may be crucial factors for intertissue communication during aging. In the present study, we investigated the expression of myokines associated with skeletal muscle aging in taurine transporter knockout (TauTKO) mice, which exhibit the accelerated skeletal muscle aging. Among transforming growth factor (TGF)-beta family genes, only growth and differentiation factor 15 (GDF15) was markedly higher (>3-fold) in skeletal muscle of old TauTKO mice compared with that of either young TauTKO mice or old wild-type mice. Circulating levels of GDF15 were also elevated in old TauTKO mice. An elevation in circulating GDF15 was also observed in very old (30-month-old) wild-type mice, while skeletal GDF15 levels were normal. The treatment of cultured mouse C2C12 myotubular cells with aging-related factors that mediate cellular stresses, such as oxidative stress (hydrogen peroxide) and endoplasmic reticulum stress (tunicamycin and thapsigargin), leads to an increase in GDF15 secretion. In conclusion, GDF15 is a myokine secreted by agingrelated stress and may control aging phenotype.Key words growth differentiation factor 15 (GDF15); sarcopenia; aging cell; skeletal muscle; myokine Aging-related loss of muscle mass and strength causes physical activities of daily living and decreases the QOL.1) Additionally, it has been demonstrated that skeletal muscle mass and strength are well associated with the mortality rate and aging-related diseases in human.2-4) Moreover, several studies in mammals and fruit flies demonstrated that stress-sensing in skeletal muscle influences systemic aging and lifespan, 4) suggesting that non-autonomous communication between aged skeletal muscle and whole body may play a key role in aging process. Skeletal muscle is an endocrine organ that produce cytokines and growth factors, which is called as myokines. 5)

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“…We have reported that Wrn Dhel/Dhel mice exhibit a 20% increase in ROS levels in the liver ER enriched fractions compared with age-matched WT mice (29). The ER is the main site for the synthesis and folding of around one-third of the total proteome of a cell (66). Proper folding of nascent protein in the ER requires an oxidant environment.…”

Section: Mouse Modelmentioning

confidence: 99%

Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant WRN protein

et al. 2018

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Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase (WRN). Mice lacking part of the helicase domain of the WRN ortholog exhibit several phenotypic features of WS. In this study, we generated a Wrn mutant line that, like humans, relies entirely on dietary sources of vitamin C (ascorbate) to survive, by crossing them to mice that lack the gulonolactone oxidase enzyme required for ascorbate synthesis. In the presence of 0.01% ascorbate (w/v) in drinking water, double-mutant mice exhibited a severe reduction in lifespan, small size, sterility, osteopenia, and metabolic profiles different from wild-type (WT) mice. Although increasing the dose of ascorbate to 0.4% improved dramatically the phenotypes of double-mutant mice, the metabolic and cytokine profiles were different from age-matched WT mice. Finally, double-mutant mice treated with 0.01% ascorbate revealed a permanent activation of all the 3 branches of the ER stress response pathways due to a severe chronic oxidative stress in the ER compartment. In addition, markers associated with the ubiquitin-proteasome-dependent ER-associated degradation pathway were increased. Augmenting the dose of ascorbate reversed the activation of this pathway to WT levels rendering this pathway a potential therapeutic target in WS.-Aumailley, L., Dubois, M. J., Brennan, T. A., Garand, C., Paquet, E. R., Pignolo, R. J., Marette, A., Lebel, M. Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant WRN protein.

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Endoplasmic reticulum proteostasis impairment in aging

Cited by 172 publications

References 123 publications

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse

Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant WRN protein

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