Degradation of OPG by HtrA1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Nagahiro Ochiai
PROVIDER: PXD011338 | JPOST Repository | Sat Mar 02 00:00:00 GMT 2019
REPOSITORIES: jPOST
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Project description:Cerebral small vessel disease (CSVD) refers to a series of clinical, radiological, and pathological syndromes caused by various etiologies affecting small arteries, arterioles, venules, capillaries, and small veins in the brain. It can lead to cognitive impairment, stroke, gait abnormalities, and other neurological symptoms and signs. Globally, approximately 25% to 30% of strokes are caused by CSVD. The underlying mechanisms of CSVD are multifaceted, involving endothelial dysfunction, blood-brain barrier (BBB) inflammation, neuronal apoptosis, chronic cerebral hypoperfusion, and their complex interactions. Current treatments often fail to achieve satisfactory outcomes. Therefore, understanding the pathogenic mechanisms of CSVD is crucial for developing effective therapeutic strategies to mitigate its detrimental effects. The high-temperature requirement protease A-1 (HTRA1) mutations can cause hereditary CSVD. CSVD associated with HTRA1 mutations is referred to as HTRA1-associated CSVD. Homozygous HTRA1 mutations cause Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL), a rare hereditary CSVD that is inherited in an autosomal recessive manner. Heterozygous HTRA1 mutations can lead to Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy type 2 (CADASIL 2), also known as heterozygous HTRA1 mutation carriers. This condition is characterized by clinical manifestations such as stroke, cognitive impairment, gait abnormalities, alopecia, and spondylosis. To date, 35 pathogenic mutations in the HTRA1 gene have been reported, primarily exhibiting autosomal dominant inheritance. Current research mainly focuses on case reports and the potential pathogenic mechanisms associated with different mutation sites. HTRA1 mutations can lead to downregulation of HTRA1 mRNA and protein expression, thereby reducing HTRA1 protease activity. However, the specific morphological and functional changes associated with CSVD, especially those in endothelial cells, remain unclear. This study aims to explore the mutation spectrum and clinical phenotypes of heterozygous HTRA1 mutation carriers. By comparing whole-blood RNA sequencing (RNA-seq) analysis between heterozygous HTRA1 mutation carriers and healthy controls, we identify differentially expressed genes. Based on the RNA-seq results, we further investigate the effects of abnormal HtrA1 expression on the biological functions of mouse brain microvascular endothelial cells and mouse cognitive behavior. This study elucidates the role of HTRA1 in CSVD, providing insights into the pathogenesis and new therapeutic targets for patients with heterozygous HTRA1 mutations.
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Project description:Transforming growth factor-β (TGF-β) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-β accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice over-expressing a TGF-β responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-β signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-β1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-β signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-β could be one of the critical events controlling both neuronal maturation and developmental survival. Keywords: HtrA1 / neuronal survival / PAI-1 / TGF-β signalling / tPA
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Project description:Transforming growth factor-M-NM-2 (TGF-M-NM-2) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-M-NM-2 accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice over-expressing a TGF-M-NM-2 responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-M-NM-2 signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-M-NM-21, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-M-NM-2 signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-M-NM-2 could be one of the critical events controlling both neuronal maturation and developmental survival. Keywords: HtrA1 / neuronal survival / PAI-1 / TGF-M-NM-2 signalling / tPA Total RNA were extracted from 3 cultures of 2 DIV Human neurons. For each stage, equal amounts of each RNA were pooled and 5M-BM-5g were reverse-transcribed, labelled and hybridized on pangenomic microarrays. Each pool was hybridized in duplicate dye-swap independent experiments.
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Project description:The HTRA1 gene encoding an evolutionary conserved protein quality control factor can be epigenetically silenced or inactivated by mutation under pathologic conditions such as cancer. Recent evidence suggests that loss of HTRA1 function causes multiple phenotypes including acceleration of cell growth, delayed onset of senescence, centrosome amplification and polyploidy suggesting an implication in the regulation of the cell cycle. To address this model, we performed a large-scale proteomics study to correlate the abundance of proteins and HTRA1 levels in various cell cycle phases using label-free quantification mass spectrometry. These data indicate that the levels of 4723 proteins fluctuated in a cell cycle-dependent, 2872 in a HTRA1-dependent and 1530 in a cell cycle- and HTRA1-dependent manner. The large number of proteins affected by the modulation of HTRA1 levels support its general role in protein homeostasis. Moreover, the detected changes in protein abundance in combination with pull down data implicate HTRA1 is in numerous cell cycle events such as DNA replication, chromosome segregation and cell cycle dependent apoptosis. These results highlight the wide implications of HTRA1 in cellular physiology
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Project description:To explore the key signaling pathways that might be affected by up-regulated HTRA1, we performed RNA-seq analysis on ARPE-19 cells infected with HTRA1 adenovirus and negative control adenovirus for 24 h. Compare with control groups, there were 2810 differentially expressed genes (log2 |fold change|> 1, log10 adjusted p-values < 0.05) were identified to be associated with distinct biological processes. 1053 genes were significantly upregulated and 1757 genes were significantly downregulated in ARPE-19 cells overexpressing HTRA1. The KEGG pathways analysis of up-regulated and down-regulated genes and ranking the enrichment pathways according to the corrected p-value. In the KEGG pathways analysis of up-regulated genes, the metabolic pathways ranked first with 84 genes involved. And in the KEGG pathways analysis of down-regulated genes, the metabolic pathways ranked third with 104 genes involved. These results revealed that up-regulated HTRA1 prominently disturbed the metabolic pathways in ARPE-19 cells.
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Project description:HTRA1 proteolysis of TSP1 inhibits immune suppression in age-related macular degeneration. A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age related macular degeneration (AMD), a major cause of blindness affecting millions of individuals worldwide. Here we show that monocytes (Mo) from homozygous carriers of the 10q26 AMD-risk haplotype overexpress the High-Temperature Requirement A Serine Peptidase 1 (HTRA1), which locates to mononuclear phagocytes (MP) in eyes of patients with AMD. Elevated HTRA1 led to significant subretinal Mo persistence and promoted pathogenic MP accumulation due to the hydrolysis of Thrombospondin 1 (TSP1). Mechanistically, we demonstrate that HTRA1 separates TSP1’s two CD47- binding Valine-Valine-Methionine-sites that are necessary for efficient CD47 activation and repression of osteopontin (OPN) secretion, a mediator of inflammation and wound healing. Accordingly, OPN was overexpressed in early Mo-derived macrophages in 10q26 risk carriers and OPN deletion or inhibition fully reversed HTRA1- induced pathogenic MP persistence. Our observations provide new insights into the molecular mechanisms of MP accumulation in inflammation and show that HTRA1 resistant CD47 agonists and OPN inhibitors can provide a powerful tool to reverse HTRA1’s pro-inflammatory effect and restore retinal immune suppression in AMD, critical for retinal homeostasis.
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Project description:CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathyis) a small-vessel disease caused by loss of function mutaions of htrA1, which cleaves several extracellular matrix proteins. Here, we isolated microvessels from htra1 KO and wild type control mice to study the effect of htra1 loss of function on microvessels.
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