Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

Roscoe, Jennifer M; Sevier, Carolyn S.

doi:10.3390/cells9102314

Cited by 23 publications

(10 citation statements)

References 148 publications

(238 reference statements)

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“…Since the increased unfolded S protein in the ER would trigger the unfolded protein response (UPR), the UPR marker proteins BiP/GRP78, XBP1, and p-eIF2α were examined in RNA transfected HEK293 cells 48 h after transfection ( 23 – 25 ). The results showed that BiP/GRP78 and XBP1 were up-regulated, and the level of p-eIF2α was higher in S-(deg-S2) and S-(S2-1194) transfected cells than that of the WT and S-(deg-RBD) groups ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Glycosite-deleted mRNA of SARS-CoV-2 spike protein as a broad-spectrum vaccine

Cheng

Kung

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Development of the messenger RNA (mRNA) vaccine has emerged as an effective and speedy strategy to control the spread of new pathogens. After vaccination, the mRNA is translated into the real protein vaccine, and there is no need to manufacture the protein in vitro. However, the fate of mRNA and its posttranslational modification inside the cell may affect immune response. Here, we showed that the mRNA vaccine of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein with deletion of glycosites in the receptor-binding domain (RBD) or especially the subunit 2 (S2) domain to expose more conserved epitopes elicited stronger antibody and CD8+ T cell responses with broader protection against the alpha, beta, gamma, delta, and omicron variants, compared to the unmodified mRNA. Immunization of such mRNA resulted in accumulation of misfolded spike protein in the endoplasmic reticulum, causing the up-regulation of BiP/GRP78, XBP1, and p-eIF2α to induce cell apoptosis and strong CD8+ T cell response. In addition, dendritic cells (DCs) incubated with S2-glysosite deleted mRNA vaccine increased class I major histocompatibility complex (MHC I) expression. This study provides a direction for the development of broad-spectrum mRNA vaccines which may not be achieved with the use of expressed proteins as antigens.

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Section: Resultsmentioning

confidence: 99%

Glycosite-deleted mRNA of SARS-CoV-2 spike protein as a broad-spectrum vaccine

Cheng

Kung

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…As recently reviewed in [ 26 ], SERCA2B is the main responsible for ER Ca 2+ refilling in vascular endothelium. SERCA2 presents a cysteine residue in the cytosolic P-domain (Cys674) and a pair of cysteine thiols (Cys875 and Cys887) in the longest intralumenal loop 4 (L4) [ 159 ]. It has been shown that S-glutathionylation of Cys674 increases SERCA2B Ca 2+ pumping activity in the cardiovascular system [ 160 , 161 ].…”

Section: Ros Evoke or Modulate Intracellular Ca 2+ Release In Endothelial Cellsmentioning

confidence: 99%

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Negri¹,

Faris²,

Moccia³

2021

IJMS

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An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.

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“…Reactive oxygen species (ROS), mainly including singlet oxygen ( 1 O2), superoxide anion (O2 .− ), hydrogen peroxide (H2O2), and hydroxyl radical (HO• ), are produced endogenously as by-products of cellular metabolism primarily in the mitochondria, and serve as indispensable messengers involving in multiple physiological processes. [1][2][3][4][5][6] H2O2, as a kind of representative ROS, has received growing concern by the virtue of its oxidative damage of biomacromolecules such as proteins, liposomes and DNA when overproduced or excessively accumulated . Increasing evidence indicates that the unbalance of H2O2 homeostasis is related to various human diseases including cancers, the Alzheimer's disease, diabetes, and aging.…”

Section: Introductionmentioning

confidence: 99%