Elevated protease HtrA4 in the maternal circulation of preeclampsia may contribute to endothelial barrier disruption by cleaving key junctional protein VE-cadherin

Tseng, Esther S.; Teoh, Sonia Soo Yee; Wang, Yao; Nie, Guiying

doi:10.1016/j.placenta.2019.01.001

Cited by 14 publications

(19 citation statements)

References 11 publications

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confidence: 54%

“…Likewise, HtrA4 protein in the maternal serum is significantly elevated in early-onset preeclampsia [21][22][23] . Our studies further suggest that elevated circulating HtrA4 can adversely affect the integrity and function of maternal vascular endothelium and may play a role in the pathogenesis of preeclampsia [24][25][26][27][28] .However, to date, the normal function of HtrA4 in the human placenta is unknown. Since HtrA4 is expressed in cytotrophoblasts and syncytiotrophoblasts 22,23 , this study aimed to investigate the functional role of HtrA4 in trophoblast syncytialization.…”

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confidence: 54%

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HtrA4 is up-regulated during trophoblast syncytialization and BeWo cells fail to syncytialize without HtrA4

Mansilla

Wang

Lim

et al. 2021

Sci Rep

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The outer layer of the human placenta comprises syncytiotrophoblast, which forms through fusion of cytotrophoblasts (syncytialization), and plays a critical role in maternal–fetal communication including nutrient/oxygen transportation and hormone secretion. Impairment in syncytialization inevitably affects pregnancy outcomes. High temperature requirement factor A 4 (HtrA4) is a placental-specific protease, expressed by various trophoblasts including syncytiotrophoblast, and significantly elevated in preeclampsia at disease presentation. However, it is unknown whether HtrA4 is important for syncytialization. Here we first examined HtrA4 expression in primary human cytotrophoblasts during syncytialization which occurs spontaneously in culture, and in BeWo cells which syncytialize upon forskolin stimulation. The success of syncytialization in each model was confirmed by significant up-regulation/secretion of β-hCG, and the concurrent down-regulation of E-cadherin. In both models, HtrA4 mRNA and protein increased concomitantly with syncytialization. Furthermore, the secreted levels of β-hCG and HtrA4 correlated significantly and positively in both models. We next knocked out HtrA4 in BeWo by CRISPR/Cas9. Upon forskolin treatment, control BeWo profoundly up-regulated β-hCG and syncytin-1, down-regulated E-cadherin, and at the same time increased the formation of multinucleated cells, whereas BeWo cells without HtrA4 did not alter any of these parameters. Our data thus suggest that HtrA4 plays an essential role in syncytialization.

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supporting

confidence: 54%

mentioning

confidence: 54%

HtrA4 is up-regulated during trophoblast syncytialization and BeWo cells fail to syncytialize without HtrA4

Mansilla

Wang

Lim

et al. 2021

Sci Rep

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“…Regardless, in the human HTRA4 is highly expressed only in the placenta, setting HtrA4 apart from the other HtrAs. Studies to date suggest that HtrA4 exerts an important role in human placental development and pregnancy health, and in the pathogenesis of pregnancy complications [ 24 , 35 , 36 , 37 , 38 , 39 , 40 ], which will be discussed in detail later in this review.…”

Section: Protein Domain Architecture Tissue Distribution and Key Molecular Characteristics Of Human Htrasmentioning

confidence: 99%

“…Indeed, recombinant human HtrA4 can cleave the main surface receptor for vascular endothelial growth factor (VEGF)-A which is also known as kinase insert domain receptor (KDR), causing an inhibition of VEGF-A action and endothelial dysfunction [ 39 ]. In addition, HtrA4 can cleave the main endothelial junctional protein vascular endothelial (VE)-cadherin, disrupting cell—cell connections and inducing intercellular gaps between endothelial cells [ 40 ]. Furthermore, HtrA4 may cleave other cell surface receptors such as TGF-β type III receptor (TGFβRIII), producing soluble receptors that can inhibit TGF-β function [ 87 ].…”

Section: Function Regulation and Potential Substrates Of Human Htras And Their Involvement Of Various Diseasesmentioning

confidence: 99%

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications

Wang

Nie

2021

IJMS

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The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.

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“…Also, the PDZ domain positively in uenced the protease activity, which suggests that there is a requirement for allosteric and inter-molecular interaction network for HTRA4 functions [11]. HTRA4 has been found to be overexpressed in pre-eclampsia (PE), to and directly interact with HTRA1 and HTRA3, and to participate in the process of embryo implantation and decidualization [3,6,12,13,14]. In addition, HTRA4 can interact with antiapoptotic XIAP, caspase 9, and executioner caspase 7 to in uence apoptotic cell death by affecting cytoskeleton homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Integrated Bioinformatical Analysis Identified HTRA4 As An Immune-Related Prognostic Biomarker In The Gastric Cancer Microenvironment

Ji¹,

Dai²,

Wang³

et al. 2021

Preprint

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HtrA serine peptidase 4 (HTRA4), which belongs to the AB family of proteases/chapterones, participates in multiple signal pathways and plays an important regulatory role in some malignancies; however, its role in the prognosis and immune infiltrates of gastric cancer (GC) remains unclear. HTRA4 expression was thus investigated in tumor tissues, and its association with immune infiltrates was assessed, to determine its prognostic roles in GC patients. Data for patients with GC was collected from three GEO datasets. This study has investigated if high expression levels of HTRA4 are associated with a poor prognosis in GC patients, especially in T2,T3,N1,NI&N2&N3,M1,stage3 and HER2+ subgroups. HTRA4 was positively correlated with CD8+ T cells, CD4+ memory activated T cells, gamma delta T cells, and M2 macrophages in the GC microenvironment. Gene Ontology and Gene set Enrichment Analysis showed that HTRA4 was enriched in some immune-related pathways. High expression levels of HTRA4 were significantly correlated with tumors in the T stage, N stage, and clinical stage, as well as those of histological grade. In summary, HTRA4 was found to play a vital role in the progression of GC and may be a predictive biomarker for the survival of GC patients.

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Elevated protease HtrA4 in the maternal circulation of preeclampsia may contribute to endothelial barrier disruption by cleaving key junctional protein VE-cadherin

Cited by 14 publications

References 11 publications

HtrA4 is up-regulated during trophoblast syncytialization and BeWo cells fail to syncytialize without HtrA4

HtrA4 is up-regulated during trophoblast syncytialization and BeWo cells fail to syncytialize without HtrA4

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications

Integrated Bioinformatical Analysis Identified HTRA4 As An Immune-Related Prognostic Biomarker In The Gastric Cancer Microenvironment

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