scholarly journals Protein Disulfide Isomerases Control the Secretion of Wnt proteins

2018 ◽  
Author(s):  
Nanna Torpe ◽  
Sandeep Gopal ◽  
Oguzhan Baltaci ◽  
Lorenzo Rella ◽  
Ava Handley ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Protein Disulfide Isomerase ◽  
Critical Role ◽  
Globular Structure ◽  
Disulfide Isomerase ◽  
Animal Development ◽  
Wnt Proteins ◽  
Protein Disulfide Isomerases ◽  
Disulfide Isomerases ◽  
Protein Disulfide

SummaryAppropriate Wnt morphogen secretion is required to control animal development and homeostasis. Although correct Wnt globular structure is essential for secretion, proteins that directly mediate Wnt folding and maturation are incompletely characterized. Here, we report that protein disulfide isomerase-1 (PDI-1), a protein folding catalyst and chaperone, controls secretion of the Caenorhabditis elegans Wnt ortholog EGL-20. We find that PDI-1 function is required to correctly form an anteroposterior EGL-20/Wnt gradient during embryonic development. Further, PDI-1 performs this role in EGL-20/Wnt-producing epidermal cells to cell-non-autonomously control EGL-20/Wnt-dependent neuronal migration. Using pharmacological inhibition, we further show that PDI function is required in human cells for Wnt3a secretion, revealing a conserved role for disulfide isomerases. Together, these results demonstrate a critical role for PDIs within Wnt-producing cells to control long-range developmental events that are dependent on Wnt secretion.

scholarly journals Functional Differences in Yeast Protein Disulfide Isomerases

2001 ◽  
Vol 152 (3) ◽  
pp. 553-562 ◽  
Author(s):  
Per Nørgaard ◽  
Vibeke Westphal ◽  
Christine Tachibana ◽  
Lene Alsøe ◽  
Bjørn Holst ◽  
...  
Keyword(s):  
Protein Disulfide Isomerase ◽  
Essential Gene ◽  
Carboxypeptidase Y ◽  
Gene Encoding ◽  
Disulfide Isomerase ◽  
Functional Differences ◽  
Disulfide Isomerases ◽  
Encoding Protein ◽  
Protein Disulfide ◽  
Catalyzed Oxidation

PDI1 is the essential gene encoding protein disulfide isomerase in yeast. The Saccharomyces cerevisiae genome, however, contains four other nonessential genes with homology to PDI1: MPD1, MPD2, EUG1, and EPS1. We have investigated the effects of simultaneous deletions of these genes. In several cases, we found that the ability of the PDI1 homologues to restore viability to a pdi1-deleted strain when overexpressed was dependent on the presence of low endogenous levels of one or more of the other homologues. This shows that the homologues are not functionally interchangeable. In fact, Mpd1p was the only homologue capable of carrying out all the essential functions of Pdi1p. Furthermore, the presence of endogenous homologues with a CXXC motif in the thioredoxin-like domain is required for suppression of a pdi1 deletion by EUG1 (which contains two CXXS active site motifs). This underlines the essentiality of protein disulfide isomerase-catalyzed oxidation. Most mutant combinations show defects in carboxypeptidase Y folding as well as in glycan modification. There are, however, no significant effects on ER-associated protein degradation in the various protein disulfide isomerase-deleted strains.

Protein Disulfide Isomerase 4 Drives Docetaxel Resistance in Prostate Cancer

Chemotherapy ◽  
2020 ◽  
pp. 1-9
Author(s):  
Subo Qian ◽  
Shun Zhang ◽  
Yu Wu ◽  
Yu Ding ◽  
Xinyan Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Disulfide Isomerase ◽  
Critical Role ◽  
Potential Effect ◽  
Negative Regulator ◽  
Disulfide Isomerase ◽  
Docetaxel Resistance ◽  
Underlying Mechanisms ◽  
Short Hairpin Rnas ◽  
Protein Disulfide

<b><i>Background:</i></b> Protein disulfide isomerase 4 (PDIA4) has been reported to be closely associated with chemoresistance in several types of malignancies. But the pathogenic mechanisms of PDIA4 involved in docetaxel (DTX) resistance in prostate cancer (PCa) are still unknown. Hence, this study was conducted to evaluate the potential effect of PDIA4 on chemoresistance to DTX in PCa cells and to investigate the underlying mechanisms. <b><i>Methods:</i></b> Two types of DTX-resistant PCa cells, that is, DTX-resistant PC-3 cells (PC-3/DTXR) and C4-2B cells (C4-2B/DTXR) were developed, as well as the parental PC-3 and C4-2B cells were obtained to investigate these issues. Short hairpin RNAs targeting human PDIA4 to knockdown the expression of PDIA4 or PDIA4-expressing adenoviral vectors to overexpress the PDIA4 were transfected into PCa cells to study the underlying mechanisms of PDIA4 involving in PCa DTX resistance. <b><i>Results:</i></b> Results showed that PDIA4 exhibited a dramatic overexpression in PC-3/DTXR and C4-2B/DTXR cells. Down-regulation of PDIA4 by infecting PC-3/DTXR and C4-2B/DTXR cells with shPDIA4 lentivirus stimulated cell death by prompting apoptosis. Up-regulation of PDIA4 by infecting PC-3 and C4-2B cells with PDIA4-expressing adenovirus showed severer resistance to DTX. In addition, PDIA4 up-regulation induced phosphorylated protein kinase B (Akt) expression, while PDIA4 knockdown significantly inhibited the expression in PCa cells. <b><i>Conclusions:</i></b> Our study indicates that PDIA4 is a negative regulator of PCa cell apoptosis and plays a critical role in PCa DTX resistance by activating the Akt-signaling pathway. Thereby, it implies that targeting PDIA4 could be a potential adjuvant therapeutic approach against DTX resistance in PCa.

scholarly journals A Protein Disulfide Isomerase Controls Neuronal Migration Through Regulation of Wnt Secretion

2018 ◽  
Author(s):  
Nanna Torpe ◽  
Sandeep Gopal ◽  
Oguzhan Baltaci ◽  
Lorenzo Rella ◽  
Ava Handley ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Protein Disulfide Isomerase ◽  
Disulfide Isomerase ◽  
Protein Disulfide

scholarly journals Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2649
Author(s):  
Metis Hasipek ◽  
Dale Grabowski ◽  
Yihong Guan ◽  
Raghunandan Reddy Alugubelli ◽  
Anand D. Tiwari ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Disulfide Isomerase ◽  
Structural Integrity ◽  
Apoptotic Cell ◽  
Oral Treatment ◽  
Critical Role ◽  
Hematopoietic Stem ◽  
Myeloma Cells ◽  
Disulfide Isomerase ◽  
Protein Disulfide

Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34+ hematopoietic stem and progenitor cells. Bortezomib resistance leads to increased PDIA1 expression and thus CCF642-34 sensitivity, suggesting that proteasome inhibitor resistance leads to PDIA1 dependence for proteostasis and survival. CCF642-34 induces acute unresolvable UPR in myeloma cells, and oral treatment increased survival of mice in the syngeneic 5TGM1 model of myeloma. Results support development of CCF642-34 to selectively target the plasma cell program and overcome the treatment-refractory state in myeloma.

scholarly journals The regulation of Hypoxia-Inducible Factor-1 (HIF-1alpha) expression by Protein Disulfide Isomerase (PDI)

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246531
Author(s):  
Yukino Kobayashi ◽  
Ami Oguro ◽  
Yuta Hirata ◽  
Susumu Imaoka
Keyword(s):  
Cancer Progression ◽  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Redox State ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Disulfide Isomerase ◽  
Hypoxia Inducible Factor 1 ◽  
Protein Disulfide

Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor, plays a critical role in adaption to hypoxia, which is a major feature of diseases, including cancer. Protein disulfide isomerase (PDI) is up-regulated in numerous cancers and leads to cancer progression. PDI, a member of the TRX superfamily, regulates the transcriptional activities of several transcription factors. To investigate the mechanisms by which PDI affects the function of HIF-1alpha, the overexpression or knockdown of PDI was performed. The overexpression of PDI decreased HIF-1alpha expression in the human hepatocarcinoma cell line, Hep3B, whereas the knockdown of endogenous PDI increased its expression. NH4Cl inhibited the decrease in HIF-1alpha expression by PDI overexpression, suggesting that HIF-1alpha was degraded by the lysosomal pathway. HIF-1alpha is transferred to lysosomal membranes by heat shock cognate 70 kDa protein (HSC70). The knockdown of HSC70 abolished the decrease, and PDI facilitated the interaction between HIF-1alpha and HSC70. HIF-1alpha directly interacted with PDI. PDI exists not only in the endoplasmic reticulum (ER), but also in the cytosol. Hypoxia increased cytosolic PDI. We also investigated changes in the redox state of HIF-1alpha using PEG-maleimide, which binds to thiols synthesized from disulfide bonds by reduction. An up-shift in the HIF-1alpha band by the overexpression of PDI was detected, suggesting that PDI formed disulfide bond in HIF-1alpha. HIF-1alpha oxidized by PDI was not degraded in HSC70-knockdown cells, indicating that the formation of disulfide bond in HIF-1alpha was important for decreases in HIF-1alpha expression. To the best of our knowledge, this is the first study to show the regulation of the expression and redox state of HIF-1alpha by PDI. We also demonstrated that PDI formed disulfide bonds in HIF-1alpha 1–245 aa and decreased its expression. In conclusion, the present results showed that PDI is a novel factor regulating HIF-1alpha through lysosome-dependent degradation by changes in its redox state.

scholarly journals A Protein Disulfide Isomerase Controls Neuronal Migration through Regulation of Wnt Secretion

Cell Reports ◽  
2019 ◽  
Vol 26 (12) ◽  
pp. 3183-3190.e5 ◽  
Author(s):  
Nanna Torpe ◽  
Sandeep Gopal ◽  
Oguzhan Baltaci ◽  
Lorenzo Rella ◽  
Ava Handley ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Protein Disulfide Isomerase ◽  
Disulfide Isomerase ◽  
Protein Disulfide
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