scholarly journals Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system

2016 ◽  
Vol 473 (4) ◽  
pp. 423-434 ◽  
Author(s):  
Lisa Ulbrich ◽  
Flores Lietta Favaloro ◽  
Laura Trobiani ◽  
Valentina Marchetti ◽  
Vruti Patel ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Pc12 Cells ◽  
Target Genes ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Response Target

The expression of the autism-related mutant R451C neuroligin3 activates the three branches of the unfolded protein response in neuronal-like PC12 cells and leads to up-regulation of the response target genes BiP and CHOP.

scholarly journals XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response

2003 ◽  
Vol 23 (21) ◽  
pp. 7448-7459 ◽  
Author(s):  
Ann-Hwee Lee ◽  
Neal N. Iwakoshi ◽  
Laurie H. Glimcher
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Gene Profiling ◽  
Minor Role ◽  
Compensatory Mechanism ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
A Minor ◽  
Protein Response

ABSTRACT The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER). We have investigated here the contribution of the UPR transcription factors XBP-1, ATF6α, and ATF6β to UPR target gene expression. Gene profiling of cell lines lacking these factors yielded several XBP-1-dependent UPR target genes, all of which appear to act in the ER. These included the DnaJ/Hsp40-like genes, p58IPK, ERdj4, and HEDJ, as well as EDEM, protein disulfide isomerase-P5, and ribosome-associated membrane protein 4 (RAMP4), whereas expression of BiP was only modestly dependent on XBP-1. Surprisingly, given previous reports that enforced expression of ATF6α induced a subset of UPR target genes, cells deficient in ATF6α, ATF6β, or both had minimal defects in upregulating UPR target genes by gene profiling analysis, suggesting the presence of compensatory mechanism(s) for ATF6 in the UPR. Since cells lacking both XBP-1 and ATF6α had significantly impaired induction of select UPR target genes and ERSE reporter activation, XBP-1 and ATF6α may serve partially redundant functions. No UPR target genes that required ATF6β were identified, nor, in contrast to XBP-1 and ATF6α, did the activity of the UPRE or ERSE promoters require ATF6β, suggesting a minor role for it during the UPR. Collectively, these results suggest that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP-1. Further, our observations suggest the existence of additional, as-yet-unknown, key regulators of the UPR.

scholarly journals Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

2020 ◽  
Author(s):  
René L. Vidal ◽  
Denisse Sepulveda ◽  
Paulina Troncoso-Escudero ◽  
Paula Garcia-Huerta ◽  
Constanza Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Cell Function ◽  
Alpha Synuclein ◽  
Protective Effects ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

scholarly journals The Unfolded Protein Response Regulates Multiple Aspects of Secretory and Membrane Protein Biogenesis and Endoplasmic Reticulum Quality Control

2000 ◽  
Vol 150 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Davis T.W. Ng ◽  
Eric D. Spear ◽  
Peter Walter
Keyword(s):  
Membrane Protein ◽  
Unfolded Protein Response ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Yeast Saccharomyces Cerevisiae ◽  
Regulatory Pathways ◽  
Unfolded Protein ◽  
Protein Biogenesis ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is an intracellular signaling pathway that relays signals from the lumen of the ER to activate target genes in the nucleus. We devised a genetic screen in the yeast Saccharomyces cerevisiae to isolate mutants that are dependent on activation of the pathway for viability. Using this strategy, we isolated mutants affecting various aspects of ER function, including protein translocation, folding, glycosylation, glycosylphosphatidylinositol modification, and ER-associated protein degradation (ERAD). Extending results gleaned from the genetic studies, we demonstrate that the UPR regulates trafficking of proteins at the translocon to balance the needs of biosynthesis and ERAD. The approach also revealed connections of the UPR to other regulatory pathways. In particular, we identified SON1/RPN4, a recently described transcriptional regulator for genes encoding subunits of the proteasome. Our genetic strategy, therefore, offers a powerful means to provide insight into the physiology of the UPR and to identify novel genes with roles in many aspects of secretory and membrane protein biogenesis.

scholarly journals ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response

Blood ◽  
2008 ◽  
Vol 112 (2) ◽  
pp. 330-339 ◽  
Author(s):  
Olga V. Oskolkova ◽  
Taras Afonyushkin ◽  
Alexander Leitner ◽  
Elena von Schlieffen ◽  
Peter S. Gargalovic ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Target Genes ◽  
Critical Role ◽  
Close Relation ◽  
Individual Species ◽  
Oxidized Phospholipids ◽  
Vegf Mrna ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract We have shown previously that oxidized phospholipids (OxPLs), known to accumulate in atherosclerotic vessels, stimulate angiogenesis via induction of autocrine mediators, such as vascular endothelial growth factor (VEGF). We now address the pathways mediating up-regulation of VEGF in human endothelial cells treated with OxPLs. Analysis of structure-function relationship using individual species of OxPLs demonstrated a close relation between induction of VEGF and activation of the unfolded protein response (UPR). Inducers of UPR up-regulated VEGF, whereas inhibition of UPR by chemical chaperones or knock-down of cochaperone HTJ-1 inhibited elevation of VEGF mRNA induced by OxPLs. OxPLs induced protein expression of activating transcription factor-4 (ATF4), an important effector of UPR. Expression levels of VEGF in OxPL-treated cells strongly correlated with induction of the ATF4 target genes ATF3 and TRB3. Knocking down ATF4 was paralleled by loss of VEGF induction by OxPLs. Chromatin immunoprecipitation demonstrated that OxPLs stimulated binding of ATF4 to a regulatory site in the VEGFA gene. Taken together, these data characterize UPR and more specifically its ATF4 branch as an important mechanism mediating up-regulation of VEGF by OxPLs, and allow hypothesizing that the UPR cascade might play a role in pathologic angiogenesis in atherosclerotic plaques.

Oestrogen-driven changes in the bovine uterus are associated with activation of the unfolded protein response

2014 ◽  
Author(s):  
Mohammed A Alfattah ◽  
Paul Anthony McGettigan ◽  
John Arthur Browne ◽  
Khalid M Alkhodair ◽  
Katarzyna Pluta ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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