ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI
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ABSTRACT:
PROVIDER: PRJNA994159 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25250545_1.fastq.gz | Fastqsanger.gz | |||
| SRR25250545_2.fastq.gz | Fastqsanger.gz | |||
| SRR25250546_1.fastq.gz | Fastqsanger.gz | |||
| SRR25250546_2.fastq.gz | Fastqsanger.gz | |||
| SRR25250547_1.fastq.gz | Fastqsanger.gz |
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Project description:Protective humoral responses require that B cells successfully complete their differentiation programs even when exposed to hostile environments generated during severe infections, like the massive hemolysis triggered by malaria. The mechanisms utilized by differentiating B cells to withstand damaging conditions replete in PAMPs and DAMPs are poorly understood. Here we demonstrate that the serine-threonine kinase ROCK1 enables B cells to execute their differentiation programs upon exposure to PAMPs and high levels of heme, a critical DAMP, by controlling two key heme-regulated molecules, Bach2 and HRI. ROCK1 restrains plasma cell differentiation by phosphorylating Bach2. As B cells differentiate in the presence of PAMPs and heme, furthermore, ROCK1 limits the proinflammatory potential of B cells and restrains mTORC1 activity by controlling the assembly of multimolecular complexes that contain the adaptor p62, raptor, ripoptosome components, and molecules involved in RNA metabolism and proteostasis. ROCK1 regulates formation of these complexes by controlling the interplay between HSPs and the stress kinase HRI. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity and localization of key molecules that mediate cell-fate decisions, effector functions, and RNA and protein homeostasis. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses and these findings may be broadly relevant for infections, vaccine development, and immune-mediated diseases marked by chronic tissue damage like autoimmune disorders.
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Project description:Iron and heme play central roles in red blood cell production. However, the mechanisms by which iron and heme levels coordinate erythropoiesis remain incompletely understood. HRI is a heme-regulated kinase that controls translation by phosphorylating eIF2a. Here, we investigate the global impact of iron, heme and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. By defining the underlying changes in translation during iron and HRI deficiencies, we validate known regulators of this process, including Atf4, and identify novel pathways such as co-regulation of ribosomal protein mRNA translation. Surprisingly, we found that heme and HRI pathways, but not iron-regulated pathways, mediate the major protein translational and transcriptional responses to iron deficiency in erythroblasts in vivo and thereby identify previously unappreciated regulators of erythropoiesis. Our genome-wide study uncovers the major impact of the HRI-mediated integrated stress response for the adaptation to iron deficiency anemia.
2018-09-03 | GSE119365 | GEO
Project description:Macrophages are central in regulating iron homeostasis. Transcription repressor Bach2 regulates by heme. Here we investigated the relationship between heme-regulated Bach2 and macrophage in spleen. We found that gene expression were not many change between WT and Bach2 knock out mice in red-pulp macrophage.Our results suggest that the function of the red-pulp macrophage is not dependent on according to expression of Bach2.
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Project description:Macrophages are central in regulating iron homeostasis. Transcription repressor Bach2 regulates by heme. Here we investigated the relationship between heme-regulated Bach2 and macrophage in bone marrow. We identified RFP-positive and negative macrophage were in bone marrow. We found that RFP-positive macrophage related with iron-heme homeostasis maintenance and RPF-negative population related with immune response. In RFP positive macrophage, we also found the lysosomal heme transporter hrg-1 was Bach2 direct target gene. Our results suggest that the function of the bone marrow macrophage alters according to expression of Bach2.
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Project description:Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of beta-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase-domain focused CRISPR/Cas9-based genetic screen with a newly optimized sgRNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.
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Project description:Heme-regulated eIF2α kinase (HRI) is essential for the survival of erythroid precursors in iron and heme deficiency and it also plays a protective role in red blood cell diseases of erythroid protoporphyria and β-thalassemia. In this study, we demonstrated for the first time the impairment of GATA-1 and Fog-1 expressions in iron deficiency and the impairment of GATA-1 expression in β-thalassemia. Furthermore, HRI is necessary to maintain the GATA-1/Fog-1 induced functions in erythroid differentiation, cell cycle and cell survival by sustaining both expressions of GATA-1 and Fog-1 in iron deficiency and in β-thalassemia. Keywords: Genetic modification
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Project description:The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells.
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Project description:The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells.
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