Reversible and Rapid Transfer-RNA Deactivation as a Mechanism of Translational Repression in Stress

Czech, Andreas; Wende, Sandra; Mörl, Mario; Pan, Tao; Ignatova, Zoya

doi:10.1371/journal.pgen.1003767

Cited by 97 publications

(132 citation statements)

References 42 publications

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“…This is in contrast to our findings here that both 5= and 3= tiRNAs are selectively enriched in the novel Cyt c-RNP complex. More recently, it was shown that oxidative stress induced by arsenite treatment of HeLa cells inhibited translation elongation concomitant with ANG-mediated cleavage of the aminoacyl-ends of all tRNAs (45). This observation may explain the decreased association of Cyt c with full-length tRNAs during ANG treatment (Fig.…”

Section: Discussionmentioning

confidence: 90%

Angiogenin-Cleaved tRNA Halves Interact with Cytochrome c, Protecting Cells from Apoptosis during Osmotic Stress

Saikia

Jobava

Parisien

et al. 2014

Molecular and Cellular Biology

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254

219

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f Adaptation to changes in extracellular tonicity is essential for cell survival. However, severe or chronic hyperosmotic stress induces apoptosis, which involves cytochrome c (Cyt c) release from mitochondria and subsequent apoptosome formation. Here, we show that angiogenin-induced accumulation of tRNA halves (or tiRNAs) is accompanied by increased survival in hyperosmotically stressed mouse embryonic fibroblasts. Treatment of cells with angiogenin inhibits stress-induced formation of the apoptosome and increases the interaction of small RNAs with released Cyt c in a ribonucleoprotein (Cyt c-RNP) complex. Nextgeneration sequencing of RNA isolated from the Cyt c-RNP complex reveals that 20 tiRNAs are highly enriched in the Cyt c-RNP complex. Preferred components of this complex are 5= and 3= tiRNAs of specific isodecoders within a family of isoacceptors. We also demonstrate that Cyt c binds tiRNAs in vitro, and the pool of Cyt c-interacting RNAs binds tighter than individual tiRNAs. Finally, we show that angiogenin treatment of primary cortical neurons exposed to hyperosmotic stress also decreases apoptosis. Our findings reveal a connection between angiogenin-generated tiRNAs and cell survival in response to hyperosmotic stress and suggest a novel cellular complex involving Cyt c and tiRNAs that inhibits apoptosome formation and activity.

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Section: Discussionmentioning

confidence: 90%

Angiogenin-Cleaved tRNA Halves Interact with Cytochrome c, Protecting Cells from Apoptosis during Osmotic Stress

Saikia

Jobava

Parisien

et al. 2014

Molecular and Cellular Biology

Self Cite

254

219

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“…18 In addition, ANG cleaves the conserved singlestranded 39-CCA termini of all tRNAs, thereby promoting the deactivation of the aminoacyl-ends of tRNA and subsequently inhibiting translation. 43 Therefore, ANG participates in translation attenuation in ER-stressed cells through an original process of RNA interference which therefore expands UPR-induced mechanisms for the reduction of protein flux into the ER and comes in addition to the previously described phosphorylation of eIF2a, 44 regulated IRE1a-dependent decay of RNAs, 36 and selective mRNA release from the ER. 45 Our data also indicate that in the first hours after ER stress induction, ANG-mediated translation repression correlates with ANG dissociation from the ANG-inhibitor RNH1.…”

Section: Discussionmentioning

confidence: 98%

Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury

Mami

Bouvier

Karoui

et al. 2016

Journal of the American Society of Nephrology

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Endoplasmic reticulum (ER) stress is involved in the pathophysiology of kidney disease and aging, but the molecular bases underlying the biologic outcomes on the evolution of renal disease remain mostly unknown. Angiogenin (ANG) is a ribonuclease that promotes cellular adaptation under stress but its contribution to ER stress signaling remains elusive. In this study, we investigated the ANG-mediated contribution to the signaling and biologic outcomes of ER stress in kidney injury. ANG expression was significantly higher in samples from injured human kidneys than in samples from normal human kidneys, and in mouse and rat kidneys, ANG expression was specifically induced under ER stress. In human renal epithelial cells, ER stress induced ANG expression in a manner dependent on the activity of transcription factor XBP1, and ANG promoted cellular adaptation to ER stress through induction of stress granules and inhibition of translation. Moreover, the severity of renal lesions induced by ER stress was dramatically greater in ANG knockout mice (Ang 2/2 ) mice than in wild-type mice. These results indicate that ANG is a critical mediator of tissue adaptation to kidney injury and reveal a physiologically relevant ER stressmediated adaptive translational control mechanism.

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“…9 CCA-adding enzymes are also implicated in tRNA quality control and the stress response. [10][11][12][13] TRNT1 encodes the only human CCA-adding activity and is responsible for the maturation of both cytosolic and mitochondrial tRNAs. 11 siRNA knockdown of TRNT1 in wild-type human fibroblasts caused cytotoxicity and apoptosis (supplemental Figure 3), suggesting that eliminating TRNT1 function altogether is lethal, whereas mutations only impairing function could be disease-associated.…”

mentioning

confidence: 99%

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)

Chakraborty

Schmitz-Abe

Kennedy

et al. 2014

Blood

163

144

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Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy

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Reversible and Rapid Transfer-RNA Deactivation as a Mechanism of Translational Repression in Stress

Cited by 97 publications

References 42 publications

Angiogenin-Cleaved tRNA Halves Interact with Cytochrome c, Protecting Cells from Apoptosis during Osmotic Stress

Angiogenin-Cleaved tRNA Halves Interact with Cytochrome c, Protecting Cells from Apoptosis during Osmotic Stress

Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)

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