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The effect of deficiency of two ATF6 homologues at early developmental stage

ABSTRACT: 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.

ORGANISM(S): Oryzias latipes

PROVIDER: GSE37174 | GEO | 2013/02/20

SECONDARY ACCESSION(S): PRJNA158611

REPOSITORIES: GEO

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The effect of deficiency of two ATF6 homologues at early developmental stage

Project description:Mammalian ATF6M-NM-1/M-NM-2 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. ATF6M-NM-1- and ATF6M-NM-2-single knockout mice develop normally but ATF6M-NM-1/M-NM-2-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 ATF6M-NM-1, ATF6M-NM-2, 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 ATF6M-NM-1/M-NM-2-double knockout blocked notochord development, which was partially rescued by microinjection-mediated overexpression of the major ER chaperone BiP. Thus, ATF6M-NM-1/M-NM-2-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. Gene expression profile at stage 24 of DKO fish (ATF6a -/-b-/-) and control fish (ATF6a+/- b+/-) was determined. Two independent experiments were performed.

2013-02-20 | E-GEOD-37174 | biostudies-arrayexpress

The Unfolded Protein Response Regulator, ATF6, Promotes Mesodermal Differentiation

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

A genome wide CRISPR/Cas9 screen identifies calreticulin as a selective repressor of ATF6⍺

Project description:Activating transcription factor 6 alpha (ATF6⍺) is one of the three endoplasmic reticulum (ER) transmembrane stress sensors that mediate the unfolded protein response (UPR). Despite its significant involvement in long-term ER stress adaption, regulation of ATF6⍺ signalling is still poorly understood, possibly because its activation involves Golgi and nucleus trafficking. Here, we have generated a dual CHO-K1 ATF6⍺/IRE1⍺ reporter cell line to perform an unbiased genome-wide CRISPR/Cas9 mutagenesis screen, in the presence and absence of ER stress, to systematically profile genetic factors that specifically contribute to ATF6⍺ signalling. Anticipated and new candidate genes that regulate ATF6⍺ activation were discovered. Among these, calreticulin (CRT), a key ER luminal chaperone, emerged as a selective repressor molecule of ATF6⍺ signalling. Cells lacking CRT constitutively activated a BiP::sfGFP ATF6⍺-dependent reporter, had higher BiP levels and an increased rate of trafficking and processing of ATF6⍺. Purified CRT interacts with the luminal domain of ATF6⍺ in vitro and the two proteins co-immunoprecipitated from cell lysates. CRT depletion exposed a negative feedback loop implicating ATF6⍺ in repressing IRE1⍺ activity basally and overexpression of CRT reversed phenotype. Our data indicate that CRT, in addition to its known role as a chaperone, also serves as an ER repressor of ATF6⍺ to maintain selective regulation of the UPR.

2024-07-26 | GSE254745 | GEO

RNA sequencing of control and PTPN2 knocked down transcriptomes in EndoC- H1 cells with or without the treatment of pro-inflammatory cytokines

Project description:Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell function. Here, we assessed the global protein and individual PTP profile in the pancreas from diabetic NOD mice treated with anti-CD3 monoclonal antibody and IL-1 receptor antagonist (IL-1RA). The treatment reversed hyperglycemia compared to the anti-CD3 alone control group. We observed enhanced expression of PTPN2, a T1D candidate gene, and endoplasmic reticulum (ER) chaperones in islets from mice with reversed diabetes. To address the functional role of PTPN2 in β-cells, we generated PTPN2 deficient stem cell-derived β-like and human EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates the type I and type II IFN signalling networks, and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to modulate the Ca2+-dependent unfolded protein response in β-cells. Adenovirus-induced overexpression of PTPN2 decreased BiP expression and partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.

2022-01-21 | GSE172148 | GEO

The role of ER stress transducer ATF6 in the long bone growth

Project description:To identify the non-canocical role of ATF6α and ATF6β in the long bone growth plate, we have employed whole genome microarray expression profiling as a discovery platform.

2015-08-15 | GSE49646 | GEO

ATF6 is required for the survival of castration-resistant prostate cancer cells

Project description:To gain insight into the global ATF6 target gene profile in prostate cancer cells, we performed RNA-seq analysis in DU145 cells upon either ATF6 siRNA-mediated knockdown (siATF6) or Ceapin-A7-mediated ATF6α inhibition.

2022-03-23 | GSE199026 | GEO

A role for Elongin in Mediator recruitment at ATF6α regulated genes [Cut&Tag]

Project description:The bZIP transcription factor ATF6α is a master regulator of endoplasmic reticulum (ER) stress response genes. In this report, we identify the multifunctional RNA polymerase II transcription factor Elongin as a cofactor for ATF6α-dependent transcription activation. Biochemical studies reveal that Elongin functions at least in part by facilitating ATF6α-dependent loading of Mediator at the promoters and enhancers of ER stress response genes. Depletion of Elongin from cells leads to impaired transcription of ER stress response genes and to defects in the recruitment of Mediator and, in particular, its CDK8 kinase subunit. Taken together, these findings bring to light a new role for Elongin as a loading factor for Mediator during the ER stress response.

2021-09-01 | GSE172132 | GEO

A role for Elongin in Mediator recruitment at ATF6α regulated genes [RNA-Seq]

2021-09-01 | GSE172125 | GEO

The mechanism to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes

Project description:Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms in the ER; however, the crosstalk between these two pathways and its physiological significance remain unexplored. Here we report that SEL1L-HRD1 ERAD limits autophagy and that, when ERAD is impaired, the ER becomes fragmented containing misfolded ER proteins or aggregates, which are subsequently cleared by autophagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL) and ER chaperones such as BiP. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process controlled by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a profound cellular adaptation capability and plasticity, centered around SEL1L-HRD1 ERAD, in dealing with misfolded proteins or protein aggregates in the ER.

2023-04-25 | PXD040899 | Pride

HLA-B35 upregulates ET-1 and downregulates eNOS via ER stresss response in endothelial cells

Project description:The presence of the HLA-B35 allele has emerged as an important risk factor for the development of isolated pulmonary hypertension (iPHT) in patients with Scleroderma (SSc), however the mechanisms underlying this association have not been fully elucidated. The goal of our study was to determine the molecular mechanisms that mediate the biological effects of HLA-B35 in endothelial cells (ECs). Our data demonstrate that HLA-B35 expression at the physiological levels using via adenoviral vector resulted in a significantly increased endothelin-1 (ET-1) and a significantly decreased endothelial nitric oxide synthase (eNOS) mRNA and protein levels. Furthermore, HLA-B35 greatly upregulated expression of cytoplasmic chaperones, including heat shock proteins (HSPs) HSP70 (HSPA1A and HSPA1B) and HSP40 (DNAJB1 and DNAJB9), suggesting that HLA-B35 induced the ER stress and unfolded protein response (UPR) in ECs. Examination of selected mediators of the UPR response, including BiP (GRP78), CHOP (GADD153), ERO1 (endoplasmic reticulum oxidase) and PDI (protein disulfide isomerase) has revealed a consistent increase of BiP expression levels. Accordingly, Thapsigargin (TG), a known ER stress inducer, stimulated ET-1 mRNA and protein levels in ECs. This study suggests that HLA-B35 could contribute to endothelial cell dysfunction via ER stress mediated induction of ET-1 in patients with PHT.

2010-03-01 | GSE20055 | GEO

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