Human L-Dopa decarboxylase interaction with annexin V and expression during apoptosis

Chalatsa, Ioanna; Arvanitis, Nikolaos; Arvanitis, Demetrios A.; Tsakou, A.; Kalantzis, Evangelos D.; Vassiliou, Alice G.; Sideris, Diamantis C.; Frakolaki, Efseveia; Vassilaki, Niki; Vassilacopoulou, Dido

doi:10.1016/j.biochi.2020.08.010

Cited by 10 publications

(11 citation statements)

References 71 publications

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“…Downregulation of DDC expression was also shown to reverse the loss of cell viability of DV-infected cells observed at later hours p.i., while overexpression of DDC exacerbated the decrease in intracellular ATP levels during viral infection. This agrees with the previously reported function of DDC in cell apoptosis [24] and the implication of PI3K/AKT signaling in DDC-DV association [21,25].…”

Section: Discussionsupporting

confidence: 93%

Dengue Virus Replication Is Associated with Catecholamine Biosynthesis and Metabolism in Hepatocytes

Mpekoulis

Tsopela

Chalari

et al. 2022

Viruses

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Previously, the association between the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) and Dengue virus (DV) replication was demonstrated in liver cells and was found to be mediated at least by the interaction between DDC and phosphoinositide 3-kinase (PI3K). Here, we show that biogenic amines production and uptake impede DV replication in hepatocytes and monocytes, while the virus reduces catecholamine biosynthesis, metabolism, and transport. To examine how catecholamine biosynthesis/metabolism influences DV, first, we verified the role of DDC by altering DDC expression. DDC silencing enhanced virus replication, but not translation, attenuated the negative effect of DDC substrates on the virus and reduced the infection related cell death. Then, the role of the downstream steps of the catecholamine biosynthesis/metabolism was analyzed by chemical inhibition of the respective enzymes, application of their substrates and/or their products; moreover, reserpine, the inhibitor of the vesicular monoamine transporter 2 (VMAT2), was used to examine the role of uptake/storage of catecholamines on DV. Apart from the role of each enzyme/transporter, these studies revealed that the dopamine uptake, and not the dopamine-signaling, is responsible for the negative effect on DV. Accordingly, all treatments expected to enhance the accumulation of catecholamines in the cell cytosol suppressed DV replication. This was verified by the use of chemical inducers of catecholamine biosynthesis. Last, the cellular redox alterations due to catecholamine oxidation were not related with the inhibition of DV replication. In turn, DV apart from its negative impact on DDC, inhibits tyrosine hydroxylase, dopamine beta-hydroxylase, monoamine oxidase, and VMAT2 expression.

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Section: Discussionsupporting

confidence: 93%

Dengue Virus Replication Is Associated with Catecholamine Biosynthesis and Metabolism in Hepatocytes

Mpekoulis

Tsopela

Chalari

et al. 2022

Viruses

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“…Based on this finding and on our earlier observation that viral infection disturbs DDC-PI3K complex formation [7,11], a possible NS4B-DDC interaction could hinder the collaboration of NS4B with PI3K (CLASS III VSP34) to facilitate viral replication [102]. In addition, NS5A may regulate DDC levels by promoting its degradation, as DDC has been implicated in programmed cell death [10] and NS5A is known to counteract apoptosis in infected cells by inducing the degradation of apoptosis-related proteins, such as p53 [103] and IP3R3 [104].…”

Section: Discussionmentioning

confidence: 61%

“…Previous studies have reported the dysfunction of the dopamine and serotonin signaling pathways in the brain of HCV patients, correlating viral infection with neurological manifestations [95,96]. While the role of DDC expression regulation in the periphery remains largely unknown, novel research findings demonstrated the involvement of DDC in the apoptotic cell death of both neuronal and non-neuronal cells [10]. Previous studies from our group have also indicated the physical and functional association of DDC with PI3K, the kinase that phosphorylates AKT, regulating cell survival [11].…”

Section: Discussionmentioning

confidence: 99%

“…Such are the catecholamine dopamine (DA) and the indolamine serotonin/5-hydroxytryptamine (5-HT), produced by decarboxylation of L-3,4-dihydroxyphenylalanine (L-Dopa) and L-5-hydroxytryptophan (5-HTP), respectively. Although DDC was originally studied for its involvement in neurotransmission, it is also expressed and active in a variety of peripheral organs, including the liver [9], and has an additional physiological role in cell proliferation and apoptosis [10,11]. It has been suggested that the latter function is mediated by the physical and functional interaction of DDC with phosphatidylinositol 3-kinase (PI3K) that inhibits the kinase [11].…”

Section: Introductionmentioning

confidence: 99%

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Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway

Mpekoulis

Tsopela

Πάνος

et al. 2021

Viruses

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A bidirectional negative relationship between Hepatitis C virus (HCV) replication and gene expression of the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) was previously shown in the liver and attributed at least to an association of DDC with phosphatidylinositol 3-kinase (PI3K). Here, we report that the biosynthesis and uptake of catecholamines restrict HCV replication in hepatocytes, while HCV has developed ways to reduce catecholamine production. By employing gene silencing, chemical inhibition or induction of the catecholamine biosynthetic and metabolic enzymes and transporters, and by applying the substrates or the products of the respective enzymes, we unravel the role of the different steps of the pathway in viral infection. We also provide evidence that the effect of catecholamines on HCV is strongly related with oxidative stress that is generated by their autoxidation in the cytosol, while antioxidants or treatments that lower cytosolic catecholamine levels positively affect the virus. To counteract the effect of catecholamines, HCV, apart from the already reported effects on DDC, causes the down-regulation of tyrosine hydroxylase that encodes the rate-limiting enzyme of catecholamine biosynthesis and suppresses dopamine beta-hydroxylase mRNA and protein amounts, while increasing the catecholamine degradation enzyme monoamine oxidase. Moreover, the NS4B viral protein is implicated in the effect of HCV on the ratio of the ~50 kDa DDC monomer and a ~120 kDa DDC complex, while the NS5A protein has a negative effect on total DDC protein levels.

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“…Both dopamine and serotonin act also as neurotransmitters providing a linkage between immune and neuron systems [11]. A physiological role for DDC in cell proliferation and apoptosis has been shown [12,13]. In addition, our group was the first to unravel that DDC expression is associated with viral infections, and specifically has a negative relationship with hepatitis C (HCV) and Dengue (DENV) virus proliferation, in non-neuronal cells and in liver biopsies of HCV-infected patients [14].…”

Section: Introductionmentioning

confidence: 91%

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

et al. 2021

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L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤−0.7, p<0.001) and EPO (r≤−0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation.

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Human L-Dopa decarboxylase interaction with annexin V and expression during apoptosis

Cited by 10 publications

References 71 publications

Dengue Virus Replication Is Associated with Catecholamine Biosynthesis and Metabolism in Hepatocytes

Dengue Virus Replication Is Associated with Catecholamine Biosynthesis and Metabolism in Hepatocytes

Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

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