ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response

The unfolded protein response (UPR) pathway senses unfolded proteins and regulates proteostasis and cell fate through activity of the transcription factors ATF4, ATF6, and XBP1 within a complex network of three main branches. Here, we investigated contributions of the three branches to UPR activity...

Celý popis

Uloženo v:
Podrobná bibliografie
Vydáno v:iScience Ročník 23; číslo 2; s. 100860
Hlavní autoři: Yang, Huan, Niemeijer, Marije, van de Water, Bob, Beltman, Joost B.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 21.02.2020
Elsevier
Témata:
Biocomputational Method
Bioinformatics
Optical Imaging
Systems Biology
Optical Imaging
Biocomputational Method
Bioinformatics
Systems Biology
ISSN:2589-0042, 2589-0042
On-line přístup:Získat plný text
Tagy: Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
Popis
Shrnutí:The unfolded protein response (UPR) pathway senses unfolded proteins and regulates proteostasis and cell fate through activity of the transcription factors ATF4, ATF6, and XBP1 within a complex network of three main branches. Here, we investigated contributions of the three branches to UPR activity in single cells using microscopy-based quantification and dynamic modeling. BAC-GFP HepG2 reporter cell lines were exposed to tunicamycin, and activation of various UPR components was monitored for 24 h. We constructed a dynamic model to describe the adaptive UPR signaling network, for which incorporation of all three branches was required to match the data. Our calibrated model suggested that ATF6 shapes the early dynamics of pro-apoptotic CHOP. We confirmed this hypothesis by measurements beyond 24 h, by perturbing single siRNA knockdowns and by ATF6 measurements. Overall, our work indicates that ATF6 is an important regulator of CHOP, which in turn regulates cell fate decisions. [Display omitted] •A mathematical model of the unfolded protein response describes microscopy data•Integration of modeling and experimental work offers insights into UPR regulation•ATF6 shapes the early dynamics of the CHOP response Optical Imaging; Bioinformatics; Biocomputational Method; Systems Biology
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Lead Contact
These authors contributed equally
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.100860