Proteasome Levels and Activity in Pregnancies Complicated by Severe Preeclampsia and Hemolysis, Elevated Liver Enzymes, and Thrombocytopenia (HELLP) Syndrome
Kathryn Berryman,Catalin S. Buhimschi,Guomao Zhao,Michelle Axe,Megan Locke,Irina A. Buhimschi,Irina A. Buhimschi +6 more
TLDR
Levels and activity of circulatory proteasome and immunoproteasome (inflammatory subtype) in preeclampsia and hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome were examined to identify women with hypertensive pregnancy disorders and sPE and HELLP were characterized by significant upregulation in circulating levels and lytic activity of the prote asome that was partially explained by placental immunoproteinasome upregulation.Abstract:
Excessive accumulation of misfolded proteins was recently demonstrated in preeclampsia. We examined levels and activity of circulatory proteasome and immunoproteasome (inflammatory subtype) in preeclampsia and hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome. We analyzed samples from women with hypertensive pregnancy disorders (n=115), including preeclampsia with severe features (sPE) and HELLP syndrome, and normotensive controls (n=45). Plasma proteasome and immunoproteasome immunoreactivity were determined by quantifying the α-subunit of the 20S core and β5i (proteasome subunit beta 8 [PSMB8]), respectively. Plasma proteasome activity was analyzed with fluorogenic substrates. MG132, lactacystin, and ONX0914 were used to inhibit the circulating proteasome and immunoproteasome, respectively. Plasma cytokine profiles were evaluated by multiplex immunoassay. Placental expression of β5 (constitutive proteasome) and β5i (immunoproteasome) was interrogated by immunohistochemistry. Women with sPE had increased plasma 20S levels ( P<0.001) and elevated lytic activities (chymotrypsin-like 7-fold, caspase-like 4.2-fold, trypsin-like 2.2-fold; P <0.001 for all) compared with pregnant controls. Women with features of HELLP displayed the highest plasma proteasome levels and activity, which correlated with decreased IFN-γ (interferon-γ), and increased IL (interleukin)-8 and IL-10. In sPE and HELLP, chymotrypsin-like activity was suppressed by proteasome inhibitors including ONX0914. Compared with gestational age-matched controls, sPE placentas harbored increased β5 and β5i immunostaining in trophoblasts. β5i signal was elevated in HELLP with predominant staining in villous core, extravillous trophoblasts in placental islands, and extracellular vesicles in intervillous spaces. Pregnancy represents a state of increased proteostatic stress. sPE and HELLP were characterized by significant upregulation in circulating levels and lytic activity of the proteasome that was partially explained by placental immunoproteasome upregulation.read more
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Peptide splicing in the proteasome
Abstract: The proteasome is the major protease responsible for the production of antigenic peptides recognized by CD8+ cytolytic T cells (CTL). These peptides, generally 8–10 amino acids long, are presented at the cell surface by major histocompatibility complex (MHC) class I molecules. Originally, these peptides were believed to be solely derived from linear fragments of proteins, but this concept was challenged several years ago by the isolation of anti-tumor CTL that recognized spliced peptides, i.e. peptides composed of fragments distant in the parental protein. The splicing process was shown to occur in the proteasome through a transpeptidation reaction involving an acyl-enzyme intermediate. Here, we review the steps that led to the discovery of spliced peptides as well as the recent advances that uncover the unexpected importance of spliced peptides in the composition of the MHC class I repertoire.
Journal ArticleDOI
Dissecting human trophoblast cell transcriptional heterogeneity in preeclampsia using single-cell RNA sequencing
Tao Zhang,Qianqian Bian,Yanchun Chen,Xiaolin Wang,Shaowei Yu,Shunhua Liu,Ping Ji,Ling Li,Mandakini Shrestha,Shujun Dong,Rong Guo,Hong Zhang +11 more
TL;DR: In this article, the placenta was taken from the designated position after cesarean section and compared placental cell subsets and their transcriptional heterogeneity between preeclampsia and healthy pregnancies using the single-cell RNA-seq technology.
Journal ArticleDOI
Increase of circulating inflammatory molecules in preeclampsia, an update.
TL;DR: While the presence of inflammatory markers are slightly increased in healthy pregnancies, their significant increase in preeclampsia suggests that the balance between the inflammatory and antiinflammatory mechanisms may be disrupted by a shift towards inflammation.
Journal ArticleDOI
Bioinformatics analysis of microarray data to identify hub genes, as diagnostic biomarker of HELLP syndrome: System biology approach
Zahra Asadikalameh,Reza Maddah,M Maleknia,Zohre S Nassaj,Naseema Ali,Sepideh Azizi,Fatemeh Dastyar +6 more
TL;DR: Using the biological system approach is a way to target patients by identifying genes and molecular pathways in the pathogenesis of HELLP syndrome by investigating genes and important molecular factors.
Journal ArticleDOI
Integrated genomic analysis of proteasome alterations across 11,057 patients with 33 cancer types: clinically relevant outcomes in framework of 3P medicine
Na Li,Xianquan Zhan +1 more
TL;DR: It is revealed that proteasome played a significant and wide functional role in cancer biological processes and benefits the research and practice of PPPM in cancers.
References
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TL;DR: Major advances have been achieved recently in knowledge about the molecular organization of the 20S and 19S particles, their subunits, the proteasome's role in MHC-class 1 antigen presentation, and regulators of its activities.
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TL;DR: It is argued that preeclampsia arises when a universal maternal intravascular inflammatory response to pregnancy decompensates in particular cases, which may occur because either the stimulus or the maternal response is too strong.
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Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome)
Bahaeddine M Sibai,Mohammed K. Ramadan,Ihab M. Usta,Mostafa M. Salama,Brian M. Mercer,Steven A. Friedman +5 more
TL;DR: HELLP syndrome is associated with serious maternal morbidity, especially when it arises in the postpartum period, and there was a strong association between pulmonary edema and acute renal failure.