Cystatin D Locates in the Nucleus at Sites of Active Transcription and Modulates Gene and Protein Expression

Ferrer-Mayorga, Gemma; Álvarez-Díaz, Silvia; Valle, Noelia; Rivas, Javier De Las; Mendes, Marta; Barderas, Rodrigo; Canals, Françesc; Tapia, Olga; Casal, J. Ignacio; Lafarga, Miguel; Múñoz, Alberto

doi:10.1074/jbc.m115.660175

Cited by 28 publications

(21 citation statements)

References 44 publications

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“…Another three inflammatory markers, consisting of TGF-α, EN-RAGE, and OSM, only correlated with age in the patients and, interestingly, were also increased in the plasma from patients compared to CBD ( Figures 1B and 2B). The strongest correlation with age in CBD was observed for CDCP1, a molecule with a role in immune cell migration and chemotaxis [29][30][31], whereas in the patients, the strongest correlation was observed for CST5, a cysteine protease inhibitor which can also modulate gene transcription and protein expression [32,33]. The inflammatory markers that varied with age can be grouped according to function and are shown in Figure 2C for the two groups.…”

Section: Effects Of Age On Levels Of Inflammatory Markers In Plasmamentioning

confidence: 99%

“…Our study corroborates that CDCP shows the strongest correlation with age in healthy individuals [59], whereas CST5 (cystatin D) has the strongest correlation with age in the patients. CST5 is an inhibitor of lysosomal and secreted cysteine proteases, but can also locate to the nucleus and modify gene transcription [33]. Interestingly, CST5 is an ultra-early biomarker of traumatic brain injury [32].…”

Section: Inflammatory Markers In Psychiatric Disordersmentioning

confidence: 99%

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Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers

Bhandage

Cunningham

Jin

et al. 2019

IJMS

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Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers. Thirteen of these markers displayed augmented levels in patients compared to CBD. Twenty-one markers correlated with the age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients, as was the average plasma GABA concentration. GABA modulated the release of seven cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) from the patients. The study reveals significant changes in the plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.

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Section: Effects Of Age On Levels Of Inflammatory Markers In Plasmamentioning

confidence: 99%

Section: Inflammatory Markers In Psychiatric Disordersmentioning

confidence: 99%

Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers

Bhandage

Cunningham

Jin

et al. 2019

IJMS

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“…Cystatin D was reported to inhibit proliferation, migration and invasion of carcinoma cells (Alvarez-Díaz et al, 2009 ). In addition, it was shown that a proportion of cystatin D is targeted to cell nucleus at specific transcriptionally active chromatin sites (Ferrer-Mayorga et al, 2015 ). Type-3 cystatins are high molecular weight (60–120 kDa) proteins and have three repeated type 2-like cystatin domains (Salvesen et al, 1986 ).…”

Section: Cystatinsmentioning

confidence: 99%

Innate Immune Response in Brain, NF-Kappa B Signaling and Cystatins

Kopitar-Jerala

2015

Front. Mol. Neurosci.

103

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Recently several reports have demonstrated that innate immune response and inflammation have an important role in major neurodegenerative diseases. The activation of the NF-κB family of transcription factors is a key step in the regulation of pro inflammatory cytokine expression. Microglia and other cell types in the brain can be activated in response to endogenous danger molecules as well as aggregated proteins and brain injury. During the past couple of years several studies reported the role of cystatins in neuroinflammation and neurodegeneration. In the present review, I will summarize and analyze recent findings regarding the role of cystatins in inflammation and NF-κB activation. Type I cystatin stefin B (cystatin B) is an endogenous cysteine cathepsin inhibitor localized in the cytosol, mitochondria and nucleus. Mutations in the gene of stefin B are associated with the neurodegenerative disease known as Unverricht-Lundborg disease and microglial activation plays an important role in the pathogenesis of the disease. Stefin B deficient mice have increased caspase-11 expression and secreted higher amounts of pro-inflammatory cytokines. The increased caspase-11 gene expression, was a consequence of increased NF-κB activation.

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“…As a suppressor of lysosomal and secreted cysteine proteases, cystatin D (CST5) degrades multiple targets which contain matrix components, adhesion proteins and other proteases. 6 Cystatin D is a member of cystatin family II, which is from the cystatin superfamily. 7 It was demonstrated that CST5 expressed lowly in patients with bladder cancer and human immunodeficiency virus type 1 (HIV-1).…”

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confidence: 99%

Up‐regulated CST5 inhibits bone resorption and activation of osteoclasts in rat models of osteoporosis via suppression of the NF‐κB pathway

Wang

Zhang

et al. 2019

J Cellular Molecular Medi

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Here, we aim at exploring the effect of CST5 on bone resorption and activation of osteoclasts in osteoporosis (OP) rats through the NF‐κB pathway. Microarray analysis was used to screen the OP‐related differentially expressed genes. Osteoporosis was induced in rats by intragastric retinoic acid administration. The serum levels of tartrate‐resistant acid phosphatase (TRAP), bone alkaline phosphatase (BALP) and osteocalcin (OC) and the expression of CD61 on the surface of osteoclasts were examined. The number of osteoclasts and the number and area of resorption pits were detected. Besides, the pathological changes and bone mineral density in bone tissues of rats were assessed. Also, the relationship between CST5 and the NF‐κB pathway was identified through determining the expression of CST5, RANKL, RANK, OPG, p65 and IKB. Poorly expressed CST5 was indicated to affect the OP. CST5 elevation and inhibition of the NF‐κB pathway decreased serum levels of TRAP, BALP and OC and expression of CD61 in vivo and in vitro. In OP rats, CST5 overexpression increased trabecular bones and bone mineral density of bone tissues, but decreased trabecular separation, fat within the bone marrow cavities and the number of osteoclasts through inhibiting the NF‐κB pathway. In vivo experiments showed that CST5 elevation inhibited growth in number and area of osteoclastic resorption pits and restrained osteoclastic bone absorption by inhibiting the NF‐κB pathway. In summary, overexpression of CST5 suppresses the activation and bone resorption of osteoclasts by inhibiting the activation of the NF‐κB pathway.

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Cystatin D Locates in the Nucleus at Sites of Active Transcription and Modulates Gene and Protein Expression

Cited by 28 publications

References 44 publications

Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers

Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers

Innate Immune Response in Brain, NF-Kappa B Signaling and Cystatins

Up‐regulated CST5 inhibits bone resorption and activation of osteoclasts in rat models of osteoporosis via suppression of the NF‐κB pathway

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