scholarly journals Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ciara M Gallagher ◽  
Carolina Garri ◽  
Erica L Cain ◽  
Kenny Kean-Hooi Ang ◽  
Christopher G Wilson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Proteolytic Processing ◽  
Unfolded Protein ◽  
New Class ◽  
Cancer Models ◽  
Membrane Bound ◽  
The Unfolded Protein Response ◽  
Protein Response

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.

scholarly journals Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome

2016 ◽  
Vol 37 (3) ◽  
pp. 1069-1079 ◽  
Author(s):  
Zhui Yu ◽  
Huaxin Sheng ◽  
Shuai Liu ◽  
Shengli Zhao ◽  
Christopher C Glembotski ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Short Form ◽  
Infarct Volume ◽  
Stroke Outcome ◽  
Early Reperfusion ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Impaired function of the endoplasmic reticulum (ER stress) is a hallmark of many human diseases including stroke. To restore ER function in stressed cells, the unfolded protein response (UPR) is induced, which activates 3 ER stress sensor proteins including activating transcription factor 6 (ATF6). ATF6 is then cleaved by proteases to form the short-form ATF6 (sATF6), a transcription factor. To determine the extent to which activation of the ATF6 UPR branch defines the fate and function of neurons after stroke, we generated a conditional and tamoxifen-inducible sATF6 knock-in mouse. To express sATF6 in forebrain neurons, we crossed our sATF6 knock-in mouse line with Emx1-Cre mice to generate ATF6-KI mice. After the ATF6 branch was activated in ATF6-KI mice with tamoxifen, mice were subjected to transient middle cerebral artery occlusion. Forced activation of the ATF6 UPR branch reduced infarct volume and improved functional outcome at 24 h after stroke. Increased autophagic activity at early reperfusion time after stroke may contribute to the ATF6-mediated neuroprotection. We concluded that the ATF6 UPR branch is crucial to ischemic stroke outcome. Therefore, boosting UPR pro-survival pathways may be a promising therapeutic strategy for stroke.

scholarly journals Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

2016 ◽  
Vol 27 (9) ◽  
pp. 1536-1551 ◽  
Author(s):  
Michael E. Fusakio ◽  
Jeffrey A. Willy ◽  
Yongping Wang ◽  
Emily T. Mirek ◽  
Rana J. T. Al Baghdadi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cholesterol Metabolism ◽  
Unfolded Protein ◽  
Expression Of Genes ◽  
The Unfolded Protein Response ◽  
Protein Response

Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins—PERK (PEK/EIF2AK3), IRE1, and ATF6—is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera.

scholarly journals Coxsackievirus B3 Infection Activates the Unfolded Protein Response and Induces Apoptosis through Downregulation of p58IPK and Activation of CHOP and SREBP1

2010 ◽  
Vol 84 (17) ◽  
pp. 8446-8459 ◽  
Author(s):  
Huifang M. Zhang ◽  
Xin Ye ◽  
Yue Su ◽  
Ji Yuan ◽  
Zhen Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Hela Cells ◽  
Coxsackievirus B3 ◽  
Unfolded Protein ◽  
Caspase 12 ◽  
Cvb3 Infection ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Cardiomyocyte apoptosis is a hallmark of coxsackievirus B3 (CVB3)-induced myocarditis. We used cardiomyocytes and HeLa cells to explore the cellular response to CVB3 infection, with a focus on pathways leading to apoptosis. CVB3 infection triggered endoplasmic reticulum (ER) stress and differentially regulated the three arms of the unfolded protein response (UPR) initiated by the proximal ER stress sensors ATF6a (activating transcription factor 6a), IRE1-XBP1 (X box binding protein 1), and PERK (PKR-like ER protein kinase). Upon CVB3 infection, glucose-regulated protein 78 expression was upregulated, and in turn ATF6a and XBP1 were activated via protein cleavage and mRNA splicing, respectively. UPR activity was further confirmed by the enhanced expression of UPR target genes ERdj4 and EDEM1. Surprisingly, another UPR-associated gene, p58IPK, which often is upregulated during infections with other types of viruses, was downregulated at both mRNA and protein levels after CVB3 infection. These findings were observed similarly for uninfected Tet-On HeLa cells induced to overexpress ATF6a or XBP1. In exploring potential connections between the three UPR pathways, we found that the ATF6a-induced downregulation of p58IPK was associated with the activation of PKR (PERK) and the phosphorylation of eIF2α, suggesting that p58IPK, a negative regulator of PERK and PKR, mediates cross-talk between the ATF6a/IRE1-XBP1 and PERK arms. Finally, we found that CVB3 infection eventually produced the induction of the proapoptoic transcription factor CHOP and the activation of SREBP1 and caspase-12. Taken together, these data suggest that CVB3 infection activates UPR pathways and induces ER stress-mediated apoptosis through the suppression of P58IPK and induction/activation of CHOP, SREBP1, and caspase-12.

scholarly journals Endoplasmic Reticulum Stress-induced mRNA Splicing Permits Synthesis of Transcription Factor Hac1p/Ern4p That Activates the Unfolded Protein Response

1997 ◽  
Vol 8 (10) ◽  
pp. 1845-1862 ◽  
Author(s):  
Tetsushi Kawahara ◽  
Hideki Yanagi ◽  
Takashi Yura ◽  
Kazutoshi Mori
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Intracellular Signaling ◽  
Mrna Splicing ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Precursor Mrna

An intracellular signaling from the endoplasmic reticulum (ER) to the nucleus, called the unfolded protein response (UPR), is activated when unfolded proteins are accumulated in the ER under a variety of stress conditions (“ER stress”). We and others recently identified Hac1p/Ern4p as a transcription factor responsible for the UPR inSaccharomyces cerevisiae. It was further reported that Hac1p (238 aa) is detected only in ER-stressed cells, and its expression is mediated by unconventional splicing ofHAC1 precursor mRNA. The splicing replaces the C-terminal portion of Hac1p; it was proposed that precursor mRNA is also translated but the putative product of 230 aa is rapidly degraded by the ubiquitin–proteasome pathway. We have identified and characterized the same regulated splicing and confirmed its essential features. Contrary to the above proposal, however, we find that the 238-aa product of mature mRNA and the 230-aa-type protein tested are highly unstable with little or no difference in stability. Furthermore, we demonstrate that the absence of Hac1p in unstressed cells is due to the lack of translation of precursor mRNA. We conclude that Hac1p is synthesized as the result of ER stress-induced mRNA splicing, leading to activation of the UPR.

scholarly journals MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

2016 ◽  
Vol 36 (23) ◽  
pp. 2931-2944 ◽  
Author(s):  
David A. Hess ◽  
Katherine M. Strelau ◽  
Anju Karki ◽  
Mei Jiang ◽  
Ana C. Azevedo-Pouly ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Cell ◽  
Transcriptional Networks ◽  
Binding Studies ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 ( Bhlha15 ), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

scholarly journals Puf4 Regulates both Splicing and Decay of HXL1 mRNA Encoding the Unfolded Protein Response Transcription Factor in Cryptococcus neoformans

2015 ◽  
Vol 14 (4) ◽  
pp. 385-395 ◽  
Author(s):  
Virginia E. Glazier ◽  
Jan Naseer Kaur ◽  
Nancy T. Brown ◽  
Ashley A. Rivera ◽  
John C. Panepinto
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cryptococcus Neoformans ◽  
Content Type ◽  
Unfolded Protein ◽  
Puf Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Unconventional Splicing

ABSTRACT The endoplasmic reticulum (ER) responds to errors in protein folding or processing by induction of the unfolded protein response (UPR). During conditions of ER stress, unconventional splicing of an mRNA encoding the UPR-responsive transcription factor occurs at the ER surface, resulting in activation of the UPR. UPR activation is necessary for adaptation to ER stress and for the pathogenic fungus Cryptococcus neoformans is an absolute requirement for temperature adaptation and virulence. In this study, we have determined that C. neoformans has co-opted a conserved PUF RNA binding protein to regulate the posttranscriptional processing of the HXL1 mRNA encoding the UPR transcription factor. PUF elements were identified in both the 5′ and 3′ untranslated regions of the HXL1 transcript, and both elements bound Puf4. Deletion of PUF4 resulted in delayed unconventional splicing of HXL1 mRNA and delayed induction of Hxl1 target genes. In addition, the HXL1 transcript was stabilized in the absence of Puf4. The puf4 Δ mutant exhibited temperature sensitivity but was as virulent as the wild type, despite a reduction in fungal burden in the brains of infected mice. Our results reveal a novel regulatory role in which a PUF protein influences the unconventional splicing of the mRNA encoding the UPR-responsive transcription factor. These data suggest a unique role for a PUF protein in controlling UPR kinetics via the posttranscriptional regulation of the mRNA encoding the UPR transcription factor Hxl1.

scholarly journals Control of mammalian brain ageing by the unfolded protein response transcription factor XBP1

2020 ◽  
Author(s):  
Felipe Cabral-Miranda ◽  
Giovanni Tamburini ◽  
Gabriela Martinez ◽  
Danilo Medinas ◽  
Yannis Gerakis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Synaptic Function ◽  
Mammalian Brain ◽  
Unfolded Protein ◽  
Brain Ageing ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Brain ageing is the main risk factor to develop dementia and neurodegenerative diseases, associated with a decay in the buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway to cope with ER stress, to the functional deterioration of the brain during aging. Genetic disruption of the ER stress sensor IRE1α accelerated cognitive and motor decline during ageing. Exogenous bolstering of the UPR by overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue indicated that XBP1s expression attenuated age-related alterations to synaptic function and pathways linked to neurodegenerative diseases. Overall, our results demonstrate that strategies to manipulate the UPR in mammals may sustain healthy brain ageing.

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