The role of ER stress transducer ATF6 in the long bone growth
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE49646 | GEO | 2015/08/15
SECONDARY ACCESSION(S): PRJNA214596
REPOSITORIES: GEO
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Project description:Mammalian ATF6α/β are membrane-bound transcription factors which are activated by endoplasmic reticulum (ER) stress-induced proteolysis to upregulate various ER quality control proteins to maintain the homeostasis of the ER. ATF6α- and ATF6β-single knockout mice develop normally but ATF6α/β-double knockout causes embryonic lethality, the reason for which remains unknown. Here, we showed that medaka fish exhibits the same phenotype regarding the effects of deleting ATF6α, ATF6β, and both. Analyses revealed that ER stress occurred physiologically during early embryonic development, particularly in the brain, otic vesicle and notochord. The absence of transcriptional induction of ER chaperones in ATF6α/β-double knockout blocked notochord development, which was partially rescued by microinjection-mediated overexpression of the major ER chaperone BiP. Thus, ATF6α/β-mediated adjustment of chaperones to the increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis.
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Project description:ATF6 encodes a transcription factor that is activated during the Unfolded Protein Response to protect cells from ER stress. Loss of ATF6α and its paralog ATF6β, results in embryonic lethality, notochord dysgenesis, and in people, loss of ATF6α specifically, results in malformed neuroretina and congenital vision loss. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated the function of ATF6 in development using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a recently identified small molecule ATF6 agonist, and we inhibited ATF6 using iPSCs from patients harboring ATF6 mutations. We discovered that ATF6 suppresses pluripotency, enhances differentiation, and surprisingly, guides stem cells toward mesodermal cell fates. Our findings reveal a novel role for ATF6 during differentiation and identify a new strategy to robustly create mesodermal tissues through modulation of the ATF6 arm of the UPR.
2017-11-14 | GSE106847 | GEO
Project description:The Unfolded Protein Response (UPR) is a cascade of intracellular stress signaling from the endoplasmic reticulum (ER) that protect the cells from the stress caused by accumulation of unfolded or misfolded proteins in the ER. Activating transcription factor 6 (ATF6) is one of primary UPR transducers that remodels the stressed cells through transcriptional regulation. Although the activation mechanism and biological roles of ATF6 have been well studied, the understanding of the negative or feedback regulation of ATF6 remains elusive. In this report, we showed that ATF6 protein can be modified by small ubiquitin-like modification (SUMOylation) and that the transcriptional activity of ATF6 is negatively regulated by SUMOylation. We identified that SUMOylation of ATF6 is significantly increased in the cells expressing misfolded cystic fibrosis transmembrane conductance regulator (CFTR) encoded by the mutant human CFTR gene (dF508CFTR). Further analyses revealed two highly conserved SUMOylation motifs within the trans-activation domain of ATF6 protein of human, mouse, or rat specie. The human ATF6 protein can be SUMOylated mediated through the small ubiquitin-like modifier protein 1 (SUMO-1) and E3 SUMO-protein ligase 1 (PIAS1) at the conserved sumoylation residue Lys149 that is located at the N-terminal of the activated form of ATF6 protein. Bimolecular fluorescence complementation (BiFC) analysis confirmed that the activated ATF6 protein can be SUMOylated and that the ATF6 sumoylation occurs in the nuclei. Moreover, trans-activation reporter analysis demonstrated that SUMOylation of the ATF6 protein at the conserved residue Lys149 represses the transcriptional activity of ATF6. In summary, our study revealed a negative regulation of the UPR transducer ATF6 through post-translational SUMOylation. The information from this study will not only increase our understanding of the fine-tuning regulation of the UPR signaling but will also be informative to the modulation of the UPR for therapeutic benefits.
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Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. We isolated CD45+ cells from livers tumors (induced by HDTVi) of hepatocyte-specific nATF6 overexprerssion mice receiving anti-IgG/PD1 treatment for scRNAseq to decrible the the immune cell population.
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Project description:The unfolded protein response (UPR) is activated as a consequence of alterations to ER homeostasis. It upregulates a group of ER chaperones and cochaperones, as well as other genes that improve protein processing within the secretory pathway. The UPR effector ATF6? augments-but is not essential for-maximal induction of ER chaperones during stress, yet its role, if any, in protecting cellular function during normal development and physiology is unknown. A systematic analysis of multiple tissues from Atf6?-/- mice revealed that all tissues examined were grossly insensitive to loss of ATF6?. However, combined deletion of ATF6? and the ER cochaperone p58(IPK) resulted in synthetic embryonic lethality. These findings reveal for the first time that an intact UPR can compensate for the genetic impairment of protein folding in the ER in vivo. The also expose a role for p58(IPK) in normal embryonic development.
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Project description:The transcription factor ATF6 is held as a membrane precursor in the endoplasmic reticulum (ER), and is transported and proteolytically processed in the Golgi apparatus under conditions of unfolded protein response stress. We show that during stress, ATF6 forms an interaction with COPII, the protein complex required for vesicular traffic of cargo proteins from the ER. Using an in vitro budding reaction that recapitulates the ER-stress induced transport of ATF6, we show that no cytoplasmic proteins other than COPII are necessary for transport. ATF6 is retained in the ER by association with the chaperone BiP (GRP78). In the in vitro reaction, the ATF6-BiP complex disassembles when membranes are treated with reducing agent and ATP. A hybrid protein with the ATF6 cytoplasmic domain replaced by a constitutive sorting signal (Sec22b SNARE) retains stress-responsive transport in vivo and in vitro. These results suggest that unfolded proteins or an ER luminal -SH reactive bond controls BiP-ATF6 stability and access of ATF6 to the COPII budding machinery.
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