Physiological/pathological ramifications of transcription factors in the unfolded protein response

Han, Jaeseok; Kaufman, Randal J.

doi:10.1101/gad.297374.117

Cited by 100 publications

(95 citation statements)

References 285 publications

(277 reference statements)

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“…While most transcriptome-wide changes in total translation were driven by changes in mRNA levels, changes in DENV-only genes and IFN-induced genes were primarily driven by changes in translational efficiency. The activation of the UPR was primarily transcriptional, likely through the activation of the UPR-linked transcription factors XBP-1, ATF4, and CHOP (71)(72)(73).…”

Section: Resultsmentioning

confidence: 99%

Dengue Virus Selectively Annexes Endoplasmic Reticulum-Associated Translation Machinery as a Strategy for Co-opting Host Cell Protein Synthesis

Reid

Campos

Child

et al. 2018

J Virol

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Section: Resultsmentioning

confidence: 99%

Dengue Virus Selectively Annexes Endoplasmic Reticulum-Associated Translation Machinery as a Strategy for Co-opting Host Cell Protein Synthesis

Reid

Campos

Child

et al. 2018

J Virol

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“…The most ancient, conserved ER stress response (unfolded protein response, or UPR) is signalled through activation of the inositol‐requiring enzyme 1 (IRE1), a protein kinase and endoribonuclease (described below). Two more recent evolutionary developments in ER stress signalling include the protein kinase‐like endoplasmic reticulum kinase (PERK) and the transcription factor ATF6 It is generally believed that both active and inactive subpopulations of the three ER stress sensors co‐exist in normal cells, with the proportion of the active subfractions linked to cellular physiology and secretory pathway activity.…”

Section: Dynamic Regulation Of the Er Environment In Repsonse To Succmentioning

confidence: 92%

“…Two more recent evolutionary developments in ER stress signalling include the protein kinase-like endoplasmic reticulum kinase (PERK) and the transcription factor ATF6. [134][135][136] " It is generally believed that both active and inactive subpopulations of the three ER stress sensors co-exist in normal cells, with the proportion of the active subfractions linked to cellular physiology and secretory pathway activity. "…”

Section: Unfolded Protein Responsementioning

confidence: 99%

Biosynthesis, structure, and folding of the insulin precursor protein

Liu

Weiss

Arunagiri

et al. 2018

Diabetes Obesity Metabolism

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144

157

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Insulin synthesis in pancreatic β-cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and postprandially, exert major dynamic variation in preproinsulin biosynthesis. Accompanying upregulated translation of the insulin precursor includes elements of the endoplasmic reticulum (ER) translocation apparatus linked to successful orientation of the signal peptide, translocation and signal peptide cleavage of preproinsulin-all of which are necessary to initiate the pathway of proper proinsulin folding. Evolutionary pressures on the primary structure of proinsulin itself have preserved the efficiency of folding ("foldability"), and remarkably, these evolutionary pressures are distinct from those protecting the ultimate biological activity of insulin. Proinsulin foldability is manifest in the ER, in which the local environment is designed to assist in the overall load of proinsulin folding and to favour its disulphide bond formation (while limiting misfolding), all of which is closely tuned to ER stress response pathways that have complex (beneficial, as well as potentially damaging) effects on pancreatic β-cells. Proinsulin misfolding may occur as a consequence of exuberant proinsulin biosynthetic load in the ER, proinsulin coding sequence mutations, or genetic predispositions that lead to an altered ER folding environment. Proinsulin misfolding is a phenotype that is very much linked to deficient insulin production and diabetes, as is seen in a variety of contexts: rodent models bearing proinsulin-misfolding mutants, human patients with Mutant INS-gene-induced Diabetes of Youth (MIDY), animal models and human patients bearing mutations in critical ER resident proteins, and, quite possibly, in more common variety type 2 diabetes.

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“…; ). The UPR activates a complex program of gene expression through multiple transcriptional effectors such as ATF4, ATF6 and XBP1, to maintain cellular homeostasis under conditions of ER stress . It is therefore possible that, by analogy with Mrc1 in yeast, that suppression of DNA replication in response to ER stress via phosphorylation of Claspin serves to minimise conflicts between newly induced UPR stress response genes and ongoing replication in S phase cells.…”

Section: Role Of Claspin In Apoptosis Viral Infections and Nongenotomentioning

confidence: 99%

Claspin – checkpoint adaptor and DNA replication factor

et al. 2018

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Claspin was discovered as a Chk1-interacting protein necessary for Chk1 phosphorylation and activation by the upstream kinase, ATR, in response to DNA synthesis inhibition in Xenopus oocyte extracts. Subsequent investigations have defined a molecular model in which Claspin acts as an adaptor or scaffold protein to facilitate activation of Chk1 by ATR within a multiprotein complex that forms on single-stranded DNA at stalled replication forks and sites of DNA damage. Interestingly, Claspin is an unstable protein whose degradation via the proteasome is tightly regulated via ubiquitination and controlled by multiple ubiquitin ligases and deubiquitinases. As a result, Claspin levels fluctuate during the cell cycle, contributing to the regulation of checkpoint proficiency and playing a key role in terminating checkpoint-mediated cell cycle arrest. In addition to its role in signalling genotoxic stress, Claspin is required to maintain normal rates of replication fork progression during unperturbed DNA replication and may contribute to the regulation of replication origin firing. Consistent with this, Claspin can bind directly to DNA, with particular affinity for branched or forked molecules, and it interacts with multiple protein components of the replisome. As expected for a protein with key roles in checkpoint signalling and genome duplication, aberrations of Claspin expression and structure have been observed in cancer. Claspin is furthermore targeted to facilitate viral replication and plays a role in suppressing cellular DNA synthesis in response to nongenotoxic endoplasmic reticulum stress. Here, we review the functions and regulation of Claspin with a focus on areas of active research.

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Physiological/pathological ramifications of transcription factors in the unfolded protein response

Cited by 100 publications

References 285 publications

Dengue Virus Selectively Annexes Endoplasmic Reticulum-Associated Translation Machinery as a Strategy for Co-opting Host Cell Protein Synthesis

Dengue Virus Selectively Annexes Endoplasmic Reticulum-Associated Translation Machinery as a Strategy for Co-opting Host Cell Protein Synthesis

Biosynthesis, structure, and folding of the insulin precursor protein

Claspin – checkpoint adaptor and DNA replication factor

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