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 PDI-Regulated Disulfide Bond Formation in Protein Folding and Biomolecular Assembly

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 171
Author(s):  
Jiahui Fu ◽  
Jihui Gao ◽  
Zhongxin Liang ◽  
Dong Yang
Keyword(s):  
Protein Folding ◽  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Bond Formation ◽  
Molecular Assembly ◽  
Disulfide Bond Formation ◽  
Disulfide Isomerase ◽  
Biomolecular Assembly ◽  
Protein Disulfide

Disulfide bonds play a pivotal role in maintaining the natural structures of proteins to ensure their performance of normal biological functions. Moreover, biological molecular assembly, such as the gluten network, is also largely dependent on the intermolecular crosslinking via disulfide bonds. In eukaryotes, the formation and rearrangement of most intra- and intermolecular disulfide bonds in the endoplasmic reticulum (ER) are mediated by protein disulfide isomerases (PDIs), which consist of multiple thioredoxin-like domains. These domains assist correct folding of proteins, as well as effectively prevent the aggregation of misfolded ones. Protein misfolding often leads to the formation of pathological protein aggregations that cause many diseases. On the other hand, glutenin aggregation and subsequent crosslinking are required for the formation of a rheologically dominating gluten network. Herein, the mechanism of PDI-regulated disulfide bond formation is important for understanding not only protein folding and associated diseases, but also the formation of functional biomolecular assembly. This review systematically illustrated the process of human protein disulfide isomerase (hPDI) mediated disulfide bond formation and complemented this with the current mechanism of wheat protein disulfide isomerase (wPDI) catalyzed formation of gluten networks.

scholarly journals Protein disulfide isomerase activity is released by activated platelets

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2226-2228 ◽  
Author(s):  
K Chen ◽  
Y Lin ◽  
TC Detwiler
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Ph Dependence ◽  
Gel Filtration ◽  
Disulfide Isomerase ◽  
Isomerase Activity ◽  
Activated Platelets ◽  
Protein Disulfide ◽  
Supernatant Solution ◽  
Disulfide Isomerase Activity

Abstract The release of protein disulfide isomerase by activated platelets was hypothesized on the basis of reported intermolecular and intramolecular thiol-disulfide exchange and disulfide reduction involving released thrombospondin in the supernatant solution of activated platelets (Danishefsky, Alexander, Detwiler: Biochemistry, 23:4984, 1984; Speziale, Detwiler: J Biol Chem, 265:17859, 1990; Speziale, Detwiler: Arch Biochem Biophys 286:546, 1991). Protein disulfide isomerase activity, measured by catalysis of the renaturation of ribonuclease inactivated by randomization of disulfide bonds, was detected in the supernatant solution after platelet activation. The activity was inhibited by peptides known to inhibit protein disulfide isomerase; the peptides also inhibited formation of disulfide-linked thrombospondin- thrombin complexes. The reaction catalyzed by the supernatant solution showed a pH dependence distinct from that of the uncatalyzed reaction. The activity was excluded by a 50-Kd dialysis membrane, and it was eluted in the void volume of a gel-filtration column, indicating that it was associated with a macromolecule. The activity was not removed by centrifugation at 100,000 g for 150 minutes indicating that it was not associated with membrane microvesicles. Possible functions for the release of protein disulfide isomerase by activated platelets are discussed.

scholarly journals Localization of protein disulfide isomerase to the external surface of the platelet plasma membrane

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2168-2173 ◽  
Author(s):  
DW Essex ◽  
K Chen ◽  
M Swiatkowska
Keyword(s):  
Indirect Immunofluorescence ◽  
Blood Cells ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Immunofluorescence Microscopy ◽  
External Surface ◽  
Platelet Surface ◽  
Disulfide Isomerase ◽  
Indirect Immunofluorescence Microscopy ◽  
Protein Disulfide

Protein disulfide isomerase (PDI) is an enzyme that catalyzes the formation as well as the isomerization of disulfide bonds. In this study, antibodies against PDI were used to show PDI antigen on the platelet surface by indirect immunofluorescence microscopy and by flow cytometry. The platelets were not activated, as evidenced by the absence of staining by an antibody against P-selectin. Permeabilized platelets showed little cytosolic PDI by indirect immunofluorescence microscopy, suggesting that the majority of platelet PDI is localized to the platelet surface. PDI activity against “scrambled” RNase was shown with intact platelets. The activity was inhibited by inhibitors of PDI and by an antibody against PDI. Other blood cells showed little PDI. Platelet surface PDI may play a role in the various physiological and pathophysiologic processes in which platelets are involved.

scholarly journals The anterior gradient-2 interactome

2020 ◽  
Vol 318 (1) ◽  
pp. C40-C47 ◽  
Author(s):  
Frederic Delom ◽  
M. Aiman Mohtar ◽  
Ted Hupp ◽  
Delphine Fessart
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Protein Quality ◽  
Physiological Role ◽  
Disulfide Isomerase ◽  
Cellular Effects ◽  
Binding Partners ◽  
Protein Disulfide ◽  
Biological Outcomes

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.

scholarly journals Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

2019 ◽  
Vol 57 (4) ◽  
pp. 274-282 ◽  
Author(s):  
Shereen Georges Ghosh ◽  
Lu Wang ◽  
Martin W Breuss ◽  
Joshua D Green ◽  
Valentina Stanley ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Transmembrane Protein ◽  
Repeat Expansion ◽  
Global Developmental Delay ◽  
Disulfide Isomerase ◽  
Whole Exome ◽  
Brain Malformations ◽  
Repeat Expansions ◽  
Protein Disulfide

BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

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