Coordination of UPR-related gene expression in early plasma cells by mTORC1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593421 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10584200.fastq.gz | Fastqsanger.gz | |||
| SRR10584300.fastq.gz | Fastqsanger.gz | |||
| SRR10584201.fastq.gz | Fastqsanger.gz | |||
| SRR10584301.fastq.gz | Fastqsanger.gz | |||
| SRR10584202.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-12-05 | GSE141423 | GEO
Project description:Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation
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Project description:Early UPR-affiliated gene expression occurs before Blimp1 upregulation and independent of canonical ER-stress activated Xbp1. In linked companion studies we detailed how Xbp1-independent activation of early plasma cell specific UPR-affiliated gene expression occurs prior to Blimp1 upregulation. Having observed that these genes overlapped with canonical mTORC1 signature genes and that PC-poised marginal zone B cells have higher base line mTORC1 signaling we designed this experiment to assess the dependence of early ER-remodeling on mTORC1 signaling in plasma cell differentiation. To this end we mated mice harboring a floxed allele for the mTORC1 adapter Raptor (B6.Rptor-flox) to mice expressing a tamoxifen-inducible cre recombinase under the control of the human CD20 promoter (B6.hCD20-TamCre). These mice and their hCD20-TamCre-Rptor-wt litermates were fed oral tamoxifen in their diet for two weeks and follicular B cells were prepared for in-vitro plasma cell differentiation studies. We report here that as early as 24 hours of stimulation in culture we see a marked defect in the ability of Rptor null B cells to upregulate UPR-affiliated genes associated with plasma cell differentiation.
2019-12-05 | GSE141421 | GEO
Project description:Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.
2023-06-19 | GSE179510 | GEO
Project description:Antibody-secreting plasma cells are the terminal stage of the B-cell lineage. Plasma cell differentiation requires a major resetting of gene expression to silence the B cell transcriptional program, whilst establishing secretory function and long-term survival. The transcription factors Blimp1 and Irf4 are essential for the initial differentiation of activated B cells to antibody-secreting cells, however their function in mature plasma cells remains elusive. We have found that while Irf4 was essential for plasma cell survival, Blimp1 was dispensable. Blimp1-deficient cells retained the unique plasma cell transcriptional signature, but lost the ability to secrete antibody or to maintain the characteristic size and ultrastructure of plasma cells. Blimp1 was required for full expression of many components of the unfolded protein response (UPR), including Xbp1 and Atf6, as well as for the appropriate processing of Igh mRNA. The overlap of Blimp1 and Xbp1 function was restricted to the UPR genes, with Blimp1 uniquely regulating activity of the mTOR pathway, plasma cell size and morphology. These studies establish Blimp1 as a major regulator of the UPR pathway that is also required for the unique metabolic requirements of plasma cells enabling the secretion of protective antibody. RNA-seq was performed on wild type, Blimp1-/- and Xbp1-/- mouse plasma cells. Between two to four biological replicates were generated and sequenced for each sample.
2016-01-18 | E-GEOD-70981 | biostudies-arrayexpress
Project description:B cells differentiate into antibody-producing plasma cells, which are critical for humoral immunity, autoimmunity, and vaccine responses. Despite the importance of environmental stressors on regulating humoral immune responses, the influence of pH on PC differentiation has not been described. Here, we identified SLC4A7, a sodium/bicarbonate cotransporter, as a selective regulator of PC differentiation. SLC4A7 deletion impaired the formation of PCs and humoral immunity to influenza A virus infection in mice. Mechanistically, we find that SLC4A7 prevents acidification of intracellular pH and thus maintains lysosomal function and mTORC1 activity. Loss of SLC4A7 suppresses PC differentiation under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Here we reveal a novel relationship between the regulation of intracellular pH by SLC4A7 and mTORC1-dependent PC differentiation and humoral immunity.
2024-06-14 | GSE269509 | GEO
Project description:Antibody-secreting plasma cells are the terminal stage of the B-cell lineage. Plasma cell differentiation requires a major resetting of gene expression to silence the B cell transcriptional program, whilst establishing secretory function and long-term survival. The transcription factors Blimp1 and Irf4 are essential for the initial differentiation of activated B cells to antibody-secreting cells, however their function in mature plasma cells remains elusive. We have found that while Irf4 was essential for plasma cell survival, Blimp1 was dispensable. Blimp1-deficient cells retained the unique plasma cell transcriptional signature, but lost the ability to secrete antibody or to maintain the characteristic size and ultrastructure of plasma cells. Blimp1 was required for full expression of many components of the unfolded protein response (UPR), including Xbp1 and Atf6, as well as for the appropriate processing of Igh mRNA. The overlap of Blimp1 and Xbp1 function was restricted to the UPR genes, with Blimp1 uniquely regulating activity of the mTOR pathway, plasma cell size and morphology. These studies establish Blimp1 as a major regulator of the UPR pathway that is also required for the unique metabolic requirements of plasma cells enabling the secretion of protective antibody.
2016-01-18 | GSE70981 | GEO
Project description:The NGS-associated mRNA-seq analysis was conducted to survey transcriptome changes responding to three UPR inducers (tunicamycin, DTT, & Azetidine-2-cytosine) by four double mutant of three UPR-associated transcription factors (bZIP17, bZIP28, & bZIP60) and two activators (S1P & S2P).
2018-03-07 | GSE100371 | GEO
Project description:Previous studies have indicated that the transcription signature of antibody-secreting cells is closely associated with the induction of the unfolded protein response pathway (UPR). Here we have used genome-wide and single cell analyses to examine the folding patterns of plasma cell genomes. We found that plasma cells adopt a cartwheel configuration and undergo large-scale changes in chromatin folding at genomic regions associated with a plasma cell specific transcription signature. During plasma cell differentiation, Blimp1 assembles into an inter-chromosomal transcription hub with genes associated with the UPR, biosynthesis of the endoplasmic reticulum (ER) as well as a cluster of genes linked with Alzheimer’s disease. We suggest that the assembly of the Blimp1-UPR-ER transcription hub permits the coordinate activation of a wide spectrum of genes that collectively establish plasma cell identity.
2019-04-10 | GSE113014 | GEO
Project description:During plasma cell differentiation there is activation of UPR gene expression that has been termed the physiological UPR of plasma cell differentiation. This is canonically thought to be downstream of Blimp1-mediated increases in immunoglobulin gene production and activation of the Xbp1 transcription factor by the RNA splicing activity of the ER-stress sensor IRE1α. Having observed UPR-affiliated gene expression prior to upregulation of Blimp1 as reported in the companion linked series, we endeavored to determine the necessity of Xbp1 activity in the early remodeling of the ER in nascent plasma cells. To this end, we mated mice harboring a floxed exon 2 of the Xbp1 gene (Xbp1flox) to mice expressing a tamoxifen-inducible cre recombinase under the control of the human CD20 promoter (hCD20-TamCre). These mice and their hCD20-TamCre-Xbp1wt litermates were fed oral tamoxifen in their diet for two weeks and follicular B cells were prepared for in-vitro plasma cell differentiation studies. We report here that prior to plasma cell differentiation as measured by CD138 expression, which coincides temporally with Blimp1 expression, there is no defect in UPR-affiliated gene expression in cells lacking Xbp1.
2019-12-05 | GSE141422 | GEO