Dataset Information

Different Eukaryotic Initiation Factor 2B? Mutations Lead to Various Degrees of Intolerance to the Stress of Endoplasmic Reticulum in Oligodendrocytes.

ABSTRACT: Vanishing white matter disease (VWM), a human autosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is responsible for the initiation of protein synthesis by its guanine nucleotide exchange factor (GEF) activity. Mutations of eIF2B impair GEF activity at different degree. Previous studies implied improperly activated unfolded protein response (UPR) and endoplasmic reticulum stress (ERS) participated in the pathogenesis of VWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types.ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Arg113His, p. Arg269FNx01 or p. Ser610-Asp613del in eIF2B?. A representative UPR-PERK component of activating transcription factor 4 (ATF4) was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors.The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity of p. Arg269FNx01 group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-I and LC3-II in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants after ERS induction.GEF activities in different genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion mutants showed less tolerable to ERS.

SUBMITTER: Chen N

PROVIDER: S-EPMC4733711 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Different Eukaryotic Initiation Factor 2Bε Mutations Lead to Various Degrees of Intolerance to the Stress of Endoplasmic Reticulum in Oligodendrocytes.

Chen Na N Jiang Yu-Wu YW Hao Hong-Jun HJ Ban Ting-Ting TT Gao Kai K Zhang Zhong-Bin ZB Wang Jing-Min JM Wu Ye Y

Chinese medical journal 20150701 13

<h4>Background</h4>Vanishing white matter disease (VWM), a human autosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is responsible for the initiation of protein synthesis by its guanine nucleotide exchange factor (GEF) activity. Mutations of eIF2B impair GEF activity at different degree. Previous studies implied improperly activated unfolded protein response (UPR) and endoplasmic reticulum stress (ERS) participated in the path ...[more]

PMID: 26112719

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Project description:Entamoeba histolytica is an intestinal parasite infecting over 50 million people worldwide and is the causative agent of amebic dysentery and amoebic liver abscess. In the human host, E. histolytica experiences stress brought on by nutrient deprivation and the host immune response. To be a successful parasite, E. histolytica must counter the stress; therefore, understanding the stress response may uncover new drug targets. In many systems, the stress response includes down-regulation of protein translation, which is regulated by phosphorylation of eukaryotic initiation factor (eIF-2?). Previous work has demonstrated that phosphorylation of the E. histolytica eIF-2? (EheIF-2?) increases significantly when exposed to long-term serum starvation, oxidative stress, and long-term heat shock. However, the effects of reagents that are known to induce nitrosative or endoplasmic reticulum (ER) stresses, on EheIF-2? have yet to be evaluated. Nitrosative stress is part of the host's immune response and ER stress can be caused by several physiological or pathological factors. We treated E. histolytica cells with various reagents known to induce nitrosative stress (DPTA-NONOate and SNP) or ER stress (BFA and DTT). We examined the morphology of the ER, tracked phosphorylation of EheIF-2?, and assessed protein translation in control and stressed cells. While all four stress-inducing reagents caused a global reduction in protein translation, only DTT was capable of also inducing changes in the morphology of the ER (consistent with ER stress) and phosphorylation of EheIF-2?. This suggests that DTT authentically induces ER stress in E. histolytica and that this stress is managed by the eIF-2?-based system. This was supported by the observation that cells expressing a non-phosphorylatable version of eIF-2? were also highly sensitive to DTT-stress. Since protein translation decreased in the absence of phosphorylation of eIF-2? (after treatment with DPTA-NONOate, SNP or BFA), the data also indicate that there are alternative protein-translational control pathways in E. histolytica. Overall, our study further illuminates the stress response to nitrosative stress and ER stress in E. histolytica.

Dataset Information

Different Eukaryotic Initiation Factor 2B? Mutations Lead to Various Degrees of Intolerance to the Stress of Endoplasmic Reticulum in Oligodendrocytes.

Publications

Different Eukaryotic Initiation Factor 2Bε Mutations Lead to Various Degrees of Intolerance to the Stress of Endoplasmic Reticulum in Oligodendrocytes.

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