ER stress sensor PERK drives tumor-promoting myelopoiesis by reprogramming hematopoietic progenitor cells in the spleen
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PROVIDER: PRJNA665414 | ENA |
REPOSITORIES: ENA
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Project description:The spleen, as the prominent site for extramedullary myelopoiesis in cancer, generates significant amounts of myeloid cells to promote tumor progression. Cancer-associated splenic myelopoiesis is mediated by a population of functionally distinct hematopoietic stem/progenitor cells (HSPCs) that are committed to immunosuppressive myeloid cell generation, but the molecular mechanism regulating this response remains unclear. Here, we found that HSPCs in the spleen of tumor-bearing mice exhibited accelerated protein synthesis and engaged in a robust endoplasmic reticulum (ER) stress response. Single-cell RNA sequencing showed that the ER stress response was concomitant with the myeloid-biased lineage commitment and dysfunction of HSPCs in the spleen. PKR-like ER resident kinase (PERK), a molecular sensor of ER stress, directed HSPC differentiation into myeloid-derived suppressor cells (MDSCs) via PERK–eIF2α–ATF4–C/EBPβ signaling. Inhibition of this signaling prevented the emergence of granulocyte/macrophage colony-stimulating factor-expressing HSPCs in the spleen and disrupted the positive feedback-driven splenic myelopoiesis. Consequently, a blockade of PERK abated the suppressive function of tumor-infiltrating MDSCs and increased cytotoxic T cell infiltration, reshaping the tumor microenvironment to effectively suppress disease progression and potentiate both immuno- and targeted therapies. In accordance, activation of PERK–ATF4–C/EBPβ signaling was indispensable for the differentiation of human umbilical cord blood-derived HSPCs into functionally competent MDSCs. Together, these results indicate a crucial role for the cellular ER stress sensor PERK in modulating splenic HSPC activities in cancer, suggesting novel therapeutic opportunities for targeting the tumor-promoting myeloid response at its source. Raw data are available on Genome Sequence Archive, Bioproject accession number: PRJCA003519
2022-03-04 | GSE158486 | GEO
Project description:The area of mitochondria in differentiated brown adipocytes is dramatically increased compared with that in brown pre-adipocytes. The ATP production is switched from the glycolysis pathway to the OXPHOS pathway during brown adipocyte differentiation. Endoplasmic reticulum (ER) is surrounded by mitochondria and the area of contact sites between mitochondria and the ER is increased. ER stress sensor PERK was phosphorylated during differentiation. To elucidate the mitochondria-ER crosstalk signaling mediated by PERK, RNA-sequencing analysis was performed using control siRNA- or PERK siRNA-transfected brown adipocytes.
2020-02-03 | GSE132598 | GEO
Project description:The spleen is an important site of hematopoietic stem/progenitor cell (HSPC) preconditioning and tumor-promoting myeloid cell generation in cancer, but the regulatory mechanism remains unclear. Here, we found that PKR-like endoplasmic reticulum kinase (PERK) mediated HSPC reprogramming into committed MDSC precursors in the spleen via PERK-ATF4-C/EBPβ signaling. Pharmacological and genetic inhibition of this pathway in murine and human HSPCs prevented their myeloid descendant cells from becoming MDSCs even with subsequent exposure to tumor microenvironment (TME) factors. In mice, the selective delivery of PERK antagonists to the spleen was not only sufficient but more effective than the tumor-targeted strategy in preventing MDSC activation in the tumor, leading to profound TME reshaping and tumor regression. Clinically, HSPCs in the spleen of cancer patients exhibit increased PERK signaling correlated with enhanced myelopoiesis. Our findings indicate that PERK-mediated HSPC preconditioning plays a crucial role in MDSC generation, suggesting novel spleen-targeting therapeutic opportunities for restraining the tumor-promoting myeloid response at its source.
| S-EPMC8919616 | biostudies-literature
Project description:The UPR (Unfolded Protein Response) is a well-orchestrated response to ER protein folding and processing overload, integrating both transcriptional and translational outputs. Its three arms in mammalian cells, the PERK translational response arm, together with the ATF6 and IRE1-mediated transcriptional arms, have been thoroughly investigated. Using ribosome footprint profiling, we performed a deep characterization of the gene expression programs involved in the acute and adaptive ER stress responses. We utilized MEFs (Mouse Embryonic Fibroblasts) treated with Thapsigargin for different durations, that were wither WT or PERK knockouts, to determine the role of PERK in the acute and chronic UPR. We characterized three major gene expression programs: acute induction, chronic induction, and repression, and found that they were all PERK dependent. All three programs were recapitulated in publicly available data and in NIH3T3 cells. While PERK -/- cells did not recapitulate these responses in the acute timepoints, late timepoints showed an extremely weak induction/repression, suggesting that the chronic responses in WT cells are largely PERK dependent as well. We found that most ER target proteins were significantly repressed; including transmembrane proteins, glycoproteins, and proteins with disulfide bonds. We further demonstrate the downregulation of cyclins, while the expression of the amino acid biosynthesis pathway was enhanced.
2019-03-20 | GSE118660 | GEO
Project description:Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK in vivo and in vitro. Furthermore, we confirmed that smgGDS deficiency aggravated apoptosis and ER stress in vivo and in vitro. And the ER stress inhibitor 4-Phenylbutyric acid and the inhibition of PERK phosphorylation mitigated smgGDS deficiency-induced ER stress related apoptosis following cisplatin treatment, while the eIF2α phosphorylation inhibitor could not reverse the smgGDS deficiency accelerated cell death. Furthermore, the over-expression of smgGDS could reverse the ER stress and apoptosis caused by CDDP. Overall, smgGDS regulated PERK-dependent ER stress and apoptosis, thereby influencing renal damage. This study identified a target for diagnosing and treating cisplatin-induced acute kidney injury.
2024-09-13 | GSE275317 | GEO
Project description:To identify the target genes of integrated stress reponse (ISR), we have employed whole genome microarray expression in MEF cells. ISR gene setimation under ER stress condition using Perk -/-, Atf4 -/-, eIF2a S51A mutant, Fv2E-PERK MEF cells
2015-09-01 | E-GEOD-49598 | biostudies-arrayexpress
Project description:Here we report that the Th2 cytokine IL-4 and the tumor microenvironment activated protein kinase RNA-like ER kinase (PERK) ER stress signaling cascade to promote immunosuppressive M2 activation and proliferation. Lacking PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. In addition, PERK activation mediated the upregulation of PSAT1 and serine biosynthesis via the downstream transcription factor ATF4.
2022-01-01 | GSE165836 | GEO
Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.
2012-01-20 | E-GEOD-29929 | biostudies-arrayexpress
Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK.
2012-01-20 | GSE29929 | GEO
Project description:Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK.
2022-06-13 | GSE200742 | GEO