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EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress

ABSTRACT: The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS12489 | MetaboLights | 2025-06-04

REPOSITORIES: MetaboLights

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			Action	DRS
	FL_1_NEG.mzXML	Mzxml
	FL_2_NEG.mzXML	Mzxml
	FL_3_NEG.mzXML	Mzxml
	FL_4_NEG.mzXML	Mzxml
	FL_5_NEG.mzXML	Mzxml

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Similar Datasets

EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress

Project description:The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.

2025-06-04 | MTBLS12491 | MetaboLights

EMP1 preserves hematopoietic stem cell potential under homeostasis and radiation-induced injury by alleviating ER stress [EMP1 RNA-seq]

Project description:Hematopoietic stem cells (HSCs) play a crucial role in lifelong hematopoiesis by generating all blood lineages. The long-term maintenance of HSCs relies on the regulation of endoplasmic reticulum (ER) stress at a low level. However, the precise control of ER stress in HSCs remains largely unknown. In this study, we demonstrate that suppression of ER stress enhances the in vitro maintenance and in vivo repopulation capacity of HSCs, while also protecting HSCs against radiation-induced injury. Integrated multi-omics analysis has revealed that epithelial membrane protein 1 (Emp1) functions as an ER stress sensor in HSCs. Loss of Emp1 leads to increased protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of dihydroceramides (dhCers), which are a class of sphingolipids. DhCers accumulate in Emp1-deficient HSCs and directly induce protein aggregation. Inhibition of CERS2 significantly restores the maintenance of Emp1-deficient HSCs. Furthermore, Emp1 deficiency renders HSCs more susceptible to radiation, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against radiation-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential, uncovering a new link between sphingolipid metabolism and HSC homeostasis, and have clinical implications.

2025-03-27 | GSE277442 | GEO

EMP1 preserves hematopoietic stem cell potential under homeostasis and radiation-induced injury by alleviating ER stress [ER-stress ATAC-seq]

2025-03-27 | GSE277444 | GEO

EMP1 preserves hematopoietic stem cell potential under homeostasis and radiation-induced injury by alleviating ER stress [ER-stress RNA-seq]

2025-03-27 | GSE277443 | GEO

Mitol dysfunction triggers apoptosis of hematopoietic stem cell via ER stress response

Project description:Cellular metabolism exceedingly determines hematopoietic stem cells (HSCs) divisional fate and functioning through organelles interaction upon stress-induced response. The outer mitochondrial membrane-localized E3 ubiquitin ligase Mitol/Marchf5 (encoded by Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and promote cell survival. To investigate the precise functional involvement of Mitol in HSC maintenance, we analyzed MX1-cre inducible Mitol knockout mice. Mitol deletion in bone marrow (BM) leads to HSCs exhaustion and impairment of BM reconstitution capability. Moreover, Mitol deletion induced prolonged ER stress in HSCs, which triggers cellular apoptosis that is mainly regulated by IRE1a signaling. Inhibition of ER stress by KIRA6 could partially reduce apoptosis of long term-HSC. Our observations indicated that Mitol is principal to maintain hematopoietic homeostasis and protects HSCs from apoptosis mainly through ER function via IRE1a signaling.

2023-12-18 | GSE240788 | GEO

Genome-wide analysis of Ischaemia-Reperfusion damage in human bowel

Project description:Comprehensive understanding of the transcriptional foundations of human intestinal ischemia-reperfusion (IR) injury is imperative to find therapeutic targets and improve patient outcome. Here we analysed transcriptomes of the IR-injured human intestine, and showed that over 1,800 genes were significantly differentially expressed, predominantly during reperfusion. Intriguingly, protein processing in endoplasmic reticulum (ER) was one of the most perturbed pathways, which was supported by ontology analysis. The IR-triggered transcriptome is organized into distinct co-expression networks, and implied a role for HIF1-alpha in the response towards unfolded proteins. Unfolded protein response activation as a consequence of ER stress was further validated in a large sample set, revealing strong correlations between expression of ER stress genes IRE1, XBP1 and BiP and autophagy gene LC3B. Moreover, signs of ER stress and autophagy, particularly ER phagy, were apparent in Paneth cells. Collectively, these findings provide new evidence for key involvement of protein folding stress in IR-induced intestinal injury in man. The ensuing ER stress, together with its manifestations in Paneth cells, likely contributes to IR-induced complications including bacterial penetration and inflammation.

2021-11-11 | GSE37013 | GEO

Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging II

Project description:Maintaining proteostasis is key to resisting stress and to promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions in proteostasis contribute stem cell aging is largely unexplored. We determined that ex vivo cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.

2021-07-11 | GSE179413 | GEO

Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging I

2021-07-11 | GSE179412 | GEO

Mitochondrial respiratory chain is essential for hematopoietic stem cell function

Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.

2017-09-13 | PXD006054 | Pride

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (ChIP_Seq)

Project description:Mitochondria have recently been identified as a critical regulator for the homeostasis of hematopoietic stem cells (HSCs). However, the mechanism underlying HSC regulation still needs to be clarified. Here, we identify transcription factor Nynrin as a novel regulator of HSC maintenance through modulation of mitochondrial function. We demonstrate that Nynrin is highly expressed in HSC under steady and stress state. Nynrin knockout leads to significantly decreased long-term HSC frequency, markedly reduced HSC dormancy, and self-renewal capacity in steady-state and stress hematopoiesis. We observed abnormal mitochondrial metabolism and mitochondrial permeability transition pore (mPTP) opening in Nynrin-deficient HSCs. Notably, Nynrin-deficient HSCs are more compromised in tolerance of irradiation- and 5-fluorouracil-induced stresses and exhibit typical phenotypes of necrosis. In contrast, overexpression of Nynrin in HSC is resistant to the radiation. Mechanistically, Nynrin deletion induces transactivation of Ppif. Overexpression of cyclophilin D (CypD), the protein encoded by the Ppif gene, causes mPTP opening, mitochondrial swelling, ROS overinduction, and cell necrosis. Both blocking the function of CypD by using cyclosporin A (CsA) or reducing the expression of Ppif could inhibit Nynrin deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in Nynrin mutant mice. Collectively, our data, for the first time, characterize Nynrin as a critical regulator of HSC function acting through the Ppif/mPTP mitochondria axis and highlight the importance of Nynrin in HSC maintenance. These data provide new insights into the mechanisms for controlling HSC fate.

2024-06-01 | GSE248635 | GEO

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