Proprotein convertase subtilisin/kexin type 9 inhibits interferon β expression through interacting with <scp>ATF</scp>‐2

Li, Zhubing; Liu, Qiang

doi:10.1002/1873-3468.13152

Cited by 9 publications

(9 citation statements)

References 40 publications

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“…This finding suggests that PCSK9 may inhibit PRRSV replication in part through up-regulation of the IFN-β product. However, this finding is not in line with the PCSK9 function reported in the previous study, in which IFN-β expression was inhibited in human cells [52]. In the previous study, PCSK9 suppressed IFN-β expression through inhibiting activating transcription factor-2 (ATF-2)/c-Jun dimerization and the binding of ATF-2/c-Jun to the IFN-β enhancer via interaction with ATF-2.…”

Section: Discussioncontrasting

confidence: 74%

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Porcine Reproductive and Respiratory Syndrome Virus Antagonizes PCSK9’s Antiviral Effect via Nsp11 Endoribonuclease Activity

Zhang

Gao

et al. 2020

Viruses

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Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the swine industry worldwide. Our previous study had indicated that proprotein convertase subtilisin/kexin type 9 (PCSK9) was a responsive gene in porcine alveolar macrophages (PAMs) upon PRRSV infection. However, whether PCSK9 impacts the PRRSV replication and how the PRRSV modulates host PCSK9 remains elusive. Here, we demonstrated that PCSK9 protein suppressed the replication of both type-1 and type-2 PRRSV species. More specifically, the C-terminal domain of PCSK9 was responsible for the antiviral activity. Besides, we showed that PCSK9 inhibited PRRSV replication by targeting the virus receptor CD163 for degradation through the lysosome. In turn, PRRSV could down-regulate the expression of PCSK9 in both PAMs and MARC-145 cells. By screening the nonstructural proteins (nsps) of PRRSV, we showed that nsp11 could antagonize PCSK9’s antiviral activity. Furthermore, mutagenic analyses of PRRSV nsp11 revealed that the endoribonuclease activity of nsp11 was critical for antagonizing the antiviral effect of PCSK9. Collectively, our data provide further insights into the interaction between PRRSV and the cell host and offer a new potential target for the antiviral therapy of PRRSV.

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Section: Discussioncontrasting

confidence: 74%

“…It has been reported that PCSK9 decreases IFN-β promoter/enhancer activity to suppress IFN-β production in humans [52]. To confirm whether the porcine PCSK9 could regulate the innate immunity response, we tested the effect of porcine PCSK9 on IFN-β production in MARC-145 cells.…”

Section: Pcsk9 Promotes Interferon Production In a Dose-dependent Mannermentioning

confidence: 99%

Porcine Reproductive and Respiratory Syndrome Virus Antagonizes PCSK9’s Antiviral Effect via Nsp11 Endoribonuclease Activity

Zhang

Gao

et al. 2020

Viruses

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“…Although data is lacking whether FH patients have an increased risk for severe COVID19, a meta-analysis suggested the potential favorable effect of lipid-lowering therapy (e.g., statins) on disease outcome ( 74 ). Other studies have indicated that PCSK9 inhibits IFNB1 expression, and contributes to dampened antiviral cellular responses in Dengue fever patients, which could be abrogated by a PCSK9 inhibitor ( 75 , 76 ). Because of the IFN enhancing effects of the PCSK9 inhibitor, the PCSK9 inhibitor was proposed as potential therapeutic for the treatment of COVID-19 ( 77 , 78 ).…”

Section: Discussionmentioning

confidence: 99%

Monocyte and Macrophage Lipid Accumulation Results in Down-Regulated Type-I Interferon Responses

Willemsen

Chen

Roomen

et al. 2022

Front. Cardiovasc. Med.

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Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The down regulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signaling pathways and suggest that this phenotype is mediated via down regulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.

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“…Barkas et al suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, through their immunomodulatory properties, may reduce the risk of serious complications of COVID-19, such as acute respiratory distress syndrome and cytokine release syndrome [ 105 ]. It is indicated that PCSK9 reduces the expression of interferon β (INF-β) [ 106 ]. Therefore, the use of PCSK9 inhibitors, especially in patients with hypercholesterolemia, should reduce this adverse effect and improve the antiviral efficiency of the organism related to INF-β [ 107 ].…”

Section: Discussionmentioning

confidence: 99%

COVID-19 and lipids. The role of lipid disorders and statin use in the prognosis of patients with SARS-CoV-2 infection

2021

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The global coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 coronavirus started in March 2020. The conclusions from numerous studies indicate that people with comorbidities, such as arterial hypertension, diabetes, obesity, underlying cardiovascular disease, are particularly vulnerable to the severe course of COVID-19. The available data also suggest that patients with dyslipidemia, the most common risk factor of cardiovascular diseases, are also at greater risk of severe course of COVID-19. On the other hand, it has been shown that COVID-19 infection has an influence on lipid profile leading to dyslipidemia, which might require appropriate treatment. Owing to antiviral, anti-inflammatory, immunomodulatory, and cardioprotective activity, statin therapy has been considered as valuable tool to improve COVID-19 outcomes. Numerous observational studies have shown potential beneficial effects of lipid-lowering treatment on the course of COVID-19 with significant improved prognosis and reduced mortality.

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Proprotein convertase subtilisin/kexin type 9 inhibits interferon β expression through interacting with ATF‐2

Cited by 9 publications

References 40 publications

Porcine Reproductive and Respiratory Syndrome Virus Antagonizes PCSK9’s Antiviral Effect via Nsp11 Endoribonuclease Activity

Porcine Reproductive and Respiratory Syndrome Virus Antagonizes PCSK9’s Antiviral Effect via Nsp11 Endoribonuclease Activity

Monocyte and Macrophage Lipid Accumulation Results in Down-Regulated Type-I Interferon Responses

COVID-19 and lipids. The role of lipid disorders and statin use in the prognosis of patients with SARS-CoV-2 infection

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