Proapoptotic Activities of Protein Disulfide Isomerase (PDI) and PDIA3 Protein, a Role of the Bcl-2 Protein Bak

Zhao, Guoping; Han, Lu; Li, Chi

doi:10.1074/jbc.m114.619353

Cited by 53 publications

(58 citation statements)

References 48 publications

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“…ER stress mediated induction of ERp57 leads to interaction with Bak and forms disulfide (-S-S-) mediated Bak oligomerization, promoting intrinsic apoptosis 11, 15, 19 . Therefore, we next determined whether ERp57 deletion in mice decreases HDM-induced -S-S- mediated oligomerization of Bak and activation of caspase-3 (apoptotic marker).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies on ER stress-mediated apoptosis have also shown involvement of ERp57 in disulfide-mediated oligomerization of proapoptotic Bak on the ER and mitochondria associated membranes 11, 15, 19, 33 . Based on the results presented herein indicating that ERp57 deleted mice showed decreased oligomerization of Bak and apoptosis marker active caspase-3, it is reasonable to speculate that ERp57 could be regulating apoptosis of epithelial cells during HDM challenge.…”

Section: Discussionmentioning

confidence: 99%

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Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

Hoffman

Chapman

Lahue

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Evidence for association between asthma and the unfolded protein response (UPR) is emerging. ERp57 is an ER localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is up regulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. Objectives Here, we sought to examine the contribution of airway epithelial-specific ERp57 in the pathogenesis of allergic asthma. Methods We examined the expression of ERp57 in human asthmatic airway epithelium and utilized murine models of allergic asthma to evaluate the relevance of epithelial- specific ERp57. Results Lung biopsies from asthmatics and non-asthmatics revealed a predominant increase in ERp57 in asthmatic epithelium. Deletion of ERp57 resulted in a significant decreases in the inflammatory cells and airways resistance in a murine model of allergic asthma. We further observed that disulfide bridges in eotaxin, EGF and periostin were also decreased in the lungs of HDM-challenged ERp57 deleted mice. Fibrotic markers such as collagen and αSMA were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for HDM-induced ER stress and airways fibrosis. Conclusions Here we show that ERp57 is increased in the airway epithelium of asthmatics and in mice with allergic airways disease. ERp57 increase is associated with redox modification of pro- inflammatory, apoptotic and fibrotic mediators, and contribute to airways hyperresposiveness (AHR). The strategies to inhibit ERp57 specifically within the airways epithelium may provide an opportunity to alleviate allergic asthma phenotype.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

Hoffman

Chapman

Lahue

et al. 2016

Journal of Allergy and Clinical Immunology

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“…In eukaryotic cells, the endoplasmic reticulum stress induces up-regulation of enzymes such as PDI to prevent the aggregation of malformed proteins [61]. Zhao and co-workers have shown that the PDI overexpression induces mitochondrial membrane permeabilization generating a proapoptotic signal [62]. It was also possible to identify differential regulation of proteins that have been associated with 7KC in the literature, such as heat shock proteins (hsp90 and hsp70).…”

Section: Accepted Manuscriptmentioning

confidence: 97%

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

Rosa-Fernandes

Stern

Cavaglieri

et al. 2017

Journal of Proteomics

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“…Ero1L-1␣ is an ER-associated protein that oxidizes PDI, which can directly catalyze the formation of disulfide bonds in folding proteins (44). The members of the PDI family of proteins act as enzymatic chaperones in the ER for misfolded proteins and can mediate apoptosis signaling through a Bak-dependent proapoptotic function (45). In the absence of Asyn expression, the activation of specific ER stress pathways identified in this system would be expected to support viral growth, support viral replication, and modulate apoptotic signaling.…”

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain

Beatman

Massey

Shives

et al. 2016

J Virol

187

176

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We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the CNS and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV infection of primary neurons, we found that Asyn protein expression is increased. The infectious titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn-knockout mice exhibited a mean increase of 10 4.5 infectious viral particles compared to the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virusinduced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease. IMPORTANCENeuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or infection of brain tissue. Following viral infection in the central nervous system, only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system. When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuron injury. Virus-induced alphasynuclein localized to intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of Parkinson's disease, these data also ascribe a novel functional role for the native expression of alpha-synuclein in the CNS.

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Proapoptotic Activities of Protein Disulfide Isomerase (PDI) and PDIA3 Protein, a Role of the Bcl-2 Protein Bak

Cited by 53 publications

References 48 publications

Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain

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