Activating transcription factor 4 and CCAAT/enhancer-binding protein-β negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress

Jin, Hyeon‐Ok; Seo, Sung‐Keum; Woo, Sang-Hyeok; Kim, Eun Sung; Lee, Hyung-Chahn; Yoo, Doo-Hyun; An, Sungkwan; Choe, Taeboo; Lee, Su‐Jae; Hong, Seok‐Il; Rhee, Chang-Hun; Kim, Jong‐il; Park, In-Chul

doi:10.1016/j.freeradbiomed.2009.01.015

Cited by 100 publications

(49 citation statements)

References 39 publications

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“…Protein translation induced by mTORC1 may result in the overloading of newly synthesized polypeptides into the ER, thus inducing the ER stress response. Conversely, the ER stress response induces eIF-2␣ phosphorylation to attenuate protein translation and can negatively regulate the mTORC1 pathway (17,33). It appears that the ER and mTORC1 regulate and keep each other in check in order to maintain cellular homeostasis.…”

Section: Discussionmentioning

confidence: 99%

The Human Cytomegalovirus Protein pUL38 Suppresses Endoplasmic Reticulum Stress-Mediated Cell Death Independently of Its Ability To Induce mTORC1 Activation

Zhou

Xuan

Gualberto

et al. 2011

J Virol

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As obligate intracellular parasites, viruses not only hijack cellular machinery, they also deregulate host stress responses for their infection. Human cytomegalovirus (HCMV) modulates the endoplasmic reticulum (ER) stress response, due at least in part to the viral protein pUL38, and one of the consequences is to maintain the viability of infected cells. Consequently, pUL38-deficient virus induces premature cell death during infection. In addition, pUL38 activates mammalian target of rapamycin complex 1 (mTORC1), which may also antagonize other detrimental cellular stresses (N. J. Moorman et al., Cell Host Microbe 3:253-262, 2008). It remains elusive how pUL38 inhibition of cell death is related to mTORC1 activation. In this study, we defined the interplay of the two pUL38 activities. We constructed a series of pUL38 truncation mutants based on the secondary structure prediction and evolutionary conservation of its sequence. We found that the N-terminal 239 residues of pUL38 were necessary and sufficient to block cell death induced by pUL38-deficient virus or by the ER stress inducer tunicamycin. However, this pUL38 domain was unable to activate mTORC1 when expressed alone. Importantly, small-molecule inhibitors of mTORC1, rapamycin or torin 1, did not compromise pUL38 activity to block cell death in isolation or in virus infection. Expression of a constitutively active variant of an mTORC1 activator, Rheb (Ras homolog enriched in brain), could not prevent cell death induced by pUL38-deficient virus. Collectively, we provide genetic and biochemical evidence that pUL38 prevents ER stress-induced cell death independent of its role in mTORC1 activation.

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Section: Discussionmentioning

confidence: 99%

The Human Cytomegalovirus Protein pUL38 Suppresses Endoplasmic Reticulum Stress-Mediated Cell Death Independently of Its Ability To Induce mTORC1 Activation

Zhou

Xuan

Gualberto

et al. 2011

J Virol

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“…TM-induced ER stress also down-regulates mammalian target of rapamycin complex 1 (mTORC1), which results in increased autophagy in cultured mouse embryonic fibroblasts (8). Down-regulation of mTORC1 after TM-induced ER stress was also reported to be associated with increased expression of CHOP as well as regulated in development and DNA damage responses 1 (REDD1)---an inhibitor of mTORC1 (25). Similar findings were recently reported in mouse hepatocytes (26).…”

Section: Discussionmentioning

confidence: 99%

Autophagy is involved in endoplasmic reticulum stress-induced cell death of rat hepatocytes

Zhang

Morris

Dorsett‐Martin

et al. 2013

Journal of Surgical Research

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Background Both endoplasmic reticulum (ER) stress and autophagy have been shown to display dual roles in cell survival in multiple cell lines. There is a reported but poorly understood link between ER stress, autophagy, and cell death. We hypothesized that autophagy plays a role in ER stress dependent cell death in rat hepatocytes. Materials and Methods Primary hepatocytes isolated from both lean and obese male Zucker rats were cultured and treated with tunicamycin (TM), tauroursodeoxycholic acid (TUDCA), 3-methyladenine (3MA), and wortmannin (WM) for 12 hours. The ER stress associated genes glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) were examined via quantitative real time PCR. Immunostaining with microtubule-associated protein 1 light chain 3 (LC3) as well as electron microscopy were used to evaluate autophagy activity. Trypan blue exclusion was used to determine hepatocyte cell viability. Results In both lean and steatotic hepatocytes, we found that TM induced both CHOP and GRP78 mRNA expression. Cells with increased ER stress were undergoing increased autophagy and had a significant decrease in cell viability. Both TUDCA and 3MA treatments attenuated TM induced ER stress, autophagy, and cell death, while WM treatment reduced autophagy and cell death but without changing ER stress. Conclusions These data suggest that autophagy is a likely downstream mediator of ER stress induced cell death in rat hepatocytes. Further exploration of the link between autophagy and ER stress in hepatocyte injury will yield important information that may be leveraged for treatment of liver injuries such as ischemia reperfusion.

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“…More recently, it has been shown that the UPR also leads to the transcriptional upregulation of a number of autophagyrelated genes essential for both the induction and construction of the autophagy machinery during ER stress [37,38]. Autophagy upregulation during ER stress is an essential pro-survival response and is required for the removal of unfolded proteins, protein aggregates, and damaged organelles.…”

Section: Er Stress and Cell Deathmentioning

confidence: 99%

“…Moreover, further studies identified that activation of REDD1 during ER stress depends on ATF4 and its downstream effector CCAAT/enhancer-binding protein-b (C/EBP-b) [101]. REDD1 transactivation leads to inhibition of mTOR in a TSC1/TSC2-dependent manner, that will consequently activate the autophagic pathway upon the release of ULK1 from inactive mTOR [8,101,102].…”

Section: Redd1mentioning

confidence: 99%

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress

Deegan

Saveljeva

Gorman

et al. 2012

Cell. Mol. Life Sci.

242

170

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Macroautophagy (autophagy) is a cellular catabolic process which can be described as a self-cannibalism. It serves as an essential protective response during conditions of endoplasmic reticulum (ER) stress through the bulk removal and degradation of unfolded proteins and damaged organelles; in particular, mitochondria (mitophagy) and ER (reticulophagy). Autophagy is genetically regulated and the autophagic machinery facilitates removal of damaged cell components and proteins; however, if the cell stress is acute or irreversible, cell death ensues. Despite these advances in the field, very little is known about how autophagy is initiated and how the autophagy machinery is transcriptionally regulated in response to ER stress. Some three dozen autophagy genes have been shown to be required for the correct assembly and function of the autophagic machinery; however; very little is known about how these genes are regulated by cellular stress. Here, we will review current knowledge regarding how ER stress and the unfolded protein response (UPR) induce autophagy, including description of the different autophagy-related genes which are regulated by the UPR.

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Activating transcription factor 4 and CCAAT/enhancer-binding protein-β negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress

Cited by 100 publications

References 39 publications

The Human Cytomegalovirus Protein pUL38 Suppresses Endoplasmic Reticulum Stress-Mediated Cell Death Independently of Its Ability To Induce mTORC1 Activation

The Human Cytomegalovirus Protein pUL38 Suppresses Endoplasmic Reticulum Stress-Mediated Cell Death Independently of Its Ability To Induce mTORC1 Activation

Autophagy is involved in endoplasmic reticulum stress-induced cell death of rat hepatocytes

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress

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