Dataset Information

LC-MS/MS proteomics of ETHE1 deficient patient fibroblasts_Study-1

ABSTRACT: The mitochondrial enzyme ETHE1 is a persulfide dioxygenase essential for cellular sulfide detoxification, and its deficiency causes the severe and complex inherited metabolic disorder ethylmalonic encephalopathy (EE). In spite of well-described clinical symptoms of the disease, detailed cellular and molecular characterization is still ambiguous. TMT-based large-scale proteomics was performed to broadly elucidate cellular consequences of the ETHE1 deficiency in the patient fibroblasts.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Inherited Metabolic Disorder

SUBMITTER: Johan Palmfeldt

LAB HEAD: Johan Palmfeldt

PROVIDER: PXD009880 | Pride | 2018-11-07

REPOSITORIES: Pride

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Publications

Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria.

Sahebekhtiari Navid N Fernandez-Guerra Paula P Nochi Zahra Z Carlsen Jasper J Bross Peter P Palmfeldt Johan J

Biochimica et biophysica acta. Molecular basis of disease 20181102 1

The mitochondrial enzyme ETHE1 is a persulfide dioxygenase essential for cellular sulfide detoxification, and its deficiency causes the severe and complex inherited metabolic disorder ethylmalonic encephalopathy (EE). In spite of well-described clinical symptoms of the disease, detailed cellular and molecular characterization is still ambiguous. Cellular redox regulation has been described to be influenced in ETHE1 deficient cells, and to clarify this further we applied image cytometry and detec ...[more]

PMID: 30391543

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Project description:Acute Myeloid Leukemia (AML) is characterized by the clonal expansion of immature myeloblasts originating from leukemic stem cells (LSCs) niched within the bone marrow. Bone marrow stromal cells (BMSC) and tumor-stroma interactions play a prominent role in the evolution of this disease. BMSC-mediated protection of leukemic cells involves several mechanisms, including interactions between adhesion molecules, the secretion of cytokines/chemokines and the release of extracellular vesicles produced by the surrounding non-haemopoietic BM cells. Recent studies even suggest that autophagy in the tumor stroma is associated with leukemia progression, survival and resistance. Thus, it seems widely evident that the microenvironment profile affects the prognosis and influences the efficacy of anti-cancer therapies. Yet, although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin (directing endocytosed SDC and receptor cargo back to cell surfaces and/or to endosomal intraluminal vesicles and exosomes) is known to coordinate inter-cellular communications. Using syntenin-knockout mice, we aimed to clarify the role of environmental-syntenin in the progression of AML, a disease in which the role of (tumor/host) syntenin was not yet investigated. To address the role of host-syntenin in AML, I extensively used the mouse FLB1 AML-like model (generous gift of O. Herault, Tours). Strikingly, FLB1 cells show a marked gain in aggressiveness when serially transplanted a syntenin-KO host. This aggressive behavior is cell-autonomous, as not reversed by back transplantation into WT hosts. Moreover, ‘aggressive’ FLB1 blasts, raised by education in a syntenin-negative in vivo background, are able to survive and grow in vitro in the absence of stroma, suggesting the cell-autonomous activation of survival pathways. Surprisingly, this gain of aggressiveness is not accompanied by a noticeable morphotypic or transcriptomic signature. However using quantitative proteomics we highlighted altered mRNA translational control. Aggressive FLB1 show a significant up-regulation of several factors, but most marked for EEF1A2, previously shown to have pro-oncogenic activities in various cancers..Globally, these findings are also consistent with the emerging notion that altered mRNA translational control is a critical factor in cancer development and progression.

Dataset Information

LC-MS/MS proteomics of ETHE1 deficient patient fibroblasts_Study-1

Publications

Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria.

Similar Datasets

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