Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress

Yu, Jiaojiao; Li, Tao; Liu, Yu; Wang, Xi; Zhang, J.; Xie, Wang; Shi, Guizhi; Lou, Jizhong; Wang, Likun; Wang, Chih‐Chen; Wang, Lei

doi:10.15252/embj.2019103841

Cited by 75 publications

(77 citation statements)

References 71 publications

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“…PDI is a multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds [83] or functions as a chaperone at high concentrations [84]. Recently, S357 of PDI was found to be phosphorylated by Fam20C and induce an open conformation of PDI that can bind to the lumenal domain of IRE1α and attenuate excessive IRE1α activity [85].…”

Section: Negative Feedback Loop In the Er Stress Responsementioning

confidence: 99%

Negative feedback and modern anti‐cancer strategies targeting the ER stress response

2020

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Endoplasmic reticulum (ER) stress is a cell state in which misfolded or unfolded proteins are aberrantly accumulated in the ER. ER stress induces an evolutionarily conserved adaptive response, named the ER stress response, that deploys a self-regulated machinery to maintain cellular proteostasis. However, compared to its well-established canonical activation mechanism, the negative feedback mechanisms regulating the ER stress response remain unclear and no accepted methods or markers have been established. Several studies have documented that both endogenous and exogenous insults can induce ER stress in cancer. Based on this evidence, small molecule inhibitors targeting ER stress response have been designed to kill cancer cells, with some of them showing excellent curative effects. Here, we review recent advances in our understanding of negative feedback of the ER stress response and compare the markers used to date. We also summarize therapeutic inhibitors targeting ER stress response and highlight the promises and challenges ahead.

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Section: Negative Feedback Loop In the Er Stress Responsementioning

confidence: 99%

Negative feedback and modern anti‐cancer strategies targeting the ER stress response

2020

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“…The prototype member of the family PDIA1 is localized primarily in the endoplasmic reticulum but nuclear, mitochondrial and localization on the surface of the cellular membrane has also been reported ( 43 ). PDIA1 exerts tumor-stimulating or suppressing effects being involved in a wide spectrum of physiological functions in a manner dependent on the type of tissue, microenvironmental conditions, subcellular localization and its oxidized or reduced conformation ( 10 – 12 ). To shed light on the role of the PDIA1 in breast carcinogenesis we followed a variety of ROS modulated pathways in the estrogen receptor positive MCF-7 and the ERα negative MDA-MB-231 cells under differential oxidative stress conditions in the presence or absence of PDIA1.…”

Section: Discussionmentioning

confidence: 99%

“…PDIA1 has been shown to modulate cellular oxidative stress mediating homeostasis of the antioxidant glutathione ( 8 ) and its function is regulated by cellular redox state. Specifically, PDIA1 exerts chaperone and isomerase activities in an oxidative stress-dependent manner facilitating redox-mediated regulation of protein folding ( 9 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state

et al. 2020

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Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER-mitochondria communication and the balance between pro-survival and pro-death pathways. In the current study the role of the PDIA1 family member in breast carcinogenesis was investigated by measuring ROS generation, mitochondrial membrane disruption, ATP production and HLA-G protein levels on the surface of the cellular membrane in the presence or absence of PDIA1. The results showed that this enzyme exerted pro-apoptotic effects in estrogen receptor (ERα)-positive breast cancer MCF-7 and pro-survival in triple negative breast cancer (TNBC) MDA-MB-231 cells. ATP generation was upregulated in PDIA1 -silenced MCF-7 cells and downregulated in PDIA1 -silenced MDA-MB-231 cells in a manner dependent on the cellular redox status. Furthermore, MCF-7 and MDA-MB-231 cells in the presence of PDIA1 expressed higher surface levels of the non-classical human leukocyte antigen (HLA-G) under oxidative stress conditions. Evaluation of the METABRIC datasets showed that low PDIA1 and high HLA-G mRNA expression levels correlated with longer survival in both ERα-positive and ERα-negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 vs. the HLA-G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA-G mRNA levels revealed that the longer the survival time of the ratio was high PDIA1 and low HLA-G mRNA and occurred predominantly in ERα-positive breast cancer patients whereas in the same subgroup of the ERα-negative breast cancer mainly this ratio was low PDIA1 and high HLA-G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition.

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“…Recently, we reported that PDI is specifically phosphorylated by the secretory pathway kinase Fam20C during ER stress. [ 84 ] Fam20C, the bona fide kinase for a majority of the secreted phosphoproteome, [ 85,86 ] was found to also phosphorylate and regulate Ero1α, the oxidase of PDI. [ 87 ] By mass spectrum analysis and a site‐specific antibody, we demonstrated that Ser357, located in the x ‐linker region, is a major Fam20C‐dependent phosphosite in PDI.…”

Section: Multiple Regulatory Modes Of Pdimentioning

confidence: 99%

Protein disulfide isomerase is regulated in multiple ways: Consequences for conformation, activities, and pathophysiological functions

Wang

2020

BioEssays

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Protein disulfide isomerase (PDI) is one of the most abundant and critical protein folding catalysts in the endoplasmic reticulum of eukaryotic cells. PDI consists of four thioredoxin domains and interacts with a wide range of substrate and partner proteins due to its intrinsic conformational flexibility. PDI plays multifunctional roles in a variety of pathophysiological events, both as an oxidoreductase and a molecular chaperone. Recent studies have revealed that the conformation and activity of PDI can be regulated in multiple ways, including posttranslational modification and substrate/ligand binding. Here, we summarize recent advances in understanding the function and regulation of PDI in different pathological and physiological events. We propose that the multifunctional roles of PDI are regulated by multiple mechanisms. Furthermore, we discuss future directions for the study of PDI, emphasizing how different regulatory modes are linked to the conformational changes and biological functions of PDI in the context of diverse pathophysiologies.

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Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress

Cited by 75 publications

References 71 publications

Negative feedback and modern anti‐cancer strategies targeting the ER stress response

Negative feedback and modern anti‐cancer strategies targeting the ER stress response

Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state

Protein disulfide isomerase is regulated in multiple ways: Consequences for conformation, activities, and pathophysiological functions

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