mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1–JNK pathway

Kato, Hironori; Nakajima, Shotaro; Saito, Youhei; Takahashi, Shuhei; Katoh, Ryohei; Kitamura, Masanori

doi:10.1038/cdd.2011.98

Cited by 244 publications

(239 citation statements)

References 39 publications

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“…TSC deficiency is functionally linked to mTORC2 inactivation as well as mTORC1 hyperactivation, both of which are thought to be major players of TSC disease (8,13). Previous studies proposed that induction of UPR is an important pathologic feature of TSC disease that contributes to critical functional abnormalities in insulin/IGF1 action and cell survival (26,40,49). These studies also suggested that mTORC1 hyperactivation by TSC deficiency increases the sensitivity of cells to ER stress-mediated death revealing an unusual property of mTOR to promote cell death under certain circumstances (26,40,49).…”

Section: Discussionmentioning

confidence: 99%

mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

Tenkerian

Krishnamoorthy

Mounir³

et al. 2015

Molecular Cancer Research

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The mTOR nucleates two complexes, namely mTOR complex 1 and 2 (mTORC1 and mTORC2), which are implicated in cell growth, survival, metabolism, and cancer. Phosphorylation of the a-subunit of translation initiation factor eIF2 at serine 51 (eIF2aS51P) is a key event of mRNA translation initiation and a master regulator of cell fate during cellular stress. Recent studies have implicated mTOR signaling in the stress response, but its connection to eIF2aS51P has remained unclear. Herein, we report that genetic as well as catalytic inhibition of mTORC2 induces eIF2aS51P. On the other hand, the allosteric inhibitor rapamycin induces eIF2aS51P through pathways that are independent of mTORC1 inactivation. Increased eIF2aS51P by impaired mTORC2 depends on the inactivation of AKT, which primes the activation of the endoplasmic reticulum (ER)-resident kinase PERK/PEK. The biologic function of eIF2aS51P was characterized in tuberous sclerosis complex (TSC)-mutant cells, which are defective in mTORC2 and AKT activity. TSC-mutant cells exhibit increased PERK activity, which is downregulated by the reconstitution of the cells with an activated form of AKT1. Also, TSCmutant cells are increasingly susceptible to ER stress, which is reversed by AKT1 reconstitution. The susceptibility of TSC-mutant cells to ER stress is further enhanced by the pharmacologic inhibition of PERK or genetic inactivation of eIF2aS51P. Thus, the PERK/eIF2aS51P arm is an important compensatory prosurvival mechanism, which substitutes for the loss of AKT under ER stress.Implications: A novel mechanistic link between mTOR function and protein synthesis is identified in TSC-null tumor cells under stress and reveals potential for the development of antitumor treatments with stress-inducing chemotherapeutics.

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Section: Discussionmentioning

confidence: 99%

mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

Tenkerian

Krishnamoorthy

Mounir³

et al. 2015

Molecular Cancer Research

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“…Interestingly, it has been further elucidated, in tubular cells, that activation of pro-apoptotic pathways can be mediated by the induction of ER stress. Not only was mTORC1 determined to function downstream of ER stress in these cells, but subsequent mTORC1 activity involved pathways culminating in IRE1-JNK activation (Kato et al 2012). Interestingly, inhibition of mTORC1 with rapamycin under the same physiological conditions selectively inhibited the IRE1 pathway.…”

Section: Adaptive Responses To a Perturbed Er In Diabetic Ptcsmentioning

confidence: 97%

“…The speculation that mTORC1 may be involved in the pathogenesis of DN came from the observation that an inhibitor of mTORC1 (rapamycin) attenuates renal hypertrophy in experimental models of DN (Sakaguchi et al 2006). Rapamycin selectively restores integrity of the podocyte foot processes through the stabilisation of the protein nephrin in the filtration barrier and reduces subsequent tubular and glomerular damage (Inoki et al 2011, Kato et al 2012. Nephrin is an integral podocyte protein involved in the retention of larger macromolecules in the blood as well as playing a role in the membrane docking of the insulin-sensitive glucose transporter, GLUT4 (Coward et al 2007).…”

Section: Mechanisms Culminating In a Stressed Diabetic Podocyte Ermentioning

confidence: 99%

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Zhuang¹,

Forbes²

2014

Journal of Endocrinology

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The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored; however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts. Key Words" endoplasmic reticulum stress " diabetic nephropathy

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“…Three to seven days after the UUO (day 3 and 7), left kidneys were removed and processed for histopathological analysis, immunohistochemistry and northern/western blot analyses. 34 In some experiments, partial UUO (mild ligature) was induced using a nylon thread (0.6 mm in diameter). 35 Individual groups contained 3-4 mice.…”

Section: Formazan Assaymentioning

confidence: 99%

“…We therefore used a mild-ligature model of UUO 34 to examine the effect of this agent at a later time period. In this experimental model, induction of collagen and a-SMA was mild, and treatment with 3 0 -deoxyadenosine modestly attenuated UUO-induced expression of type I collagen and a-SMA even at day 7 (Supplementary Figure S8).…”

Section: Lack Of Eif2a-mediated Translational Suppression For the Effmentioning

confidence: 99%

Blockade of Smad signaling by 3′-deoxyadenosine: a mechanism for its anti-fibrotic potential

Johno

Nakajima

et al. 2013

Laboratory Investigation

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Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3 0 -Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3 0 -deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3 0 -deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3 0 -deoxyadenosine on the expression of collagens triggered by transforming growth factor-b (TGF-b1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3 0 -deoxyadenosine suppressed expression of collagens induced by TGF-b1 and BMP-4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-b/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3 0 -Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2a-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3 0 -deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and a-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3 0 -deoxyadenosine interferes with the TGF-b and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3 0 -Deoxyadenosine may be useful for therapeutic intervention in various TGF-b-related fibrotic disorders.

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mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1–JNK pathway

Cited by 244 publications

References 39 publications

mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Blockade of Smad signaling by 3′-deoxyadenosine: a mechanism for its anti-fibrotic potential

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