Interactions Between Hepatitis C Virus and Proprotein Convertase Subtilisin/Kexin Type 9
Notice bibliographique
Résumé
Hepatitis C virus (HCV) is a small enveloped positive-sense single-stranded RNA virus that infects 2-3% of the world population. The majority of infected people develop chronic hepatitis, which results in severe liver damages. No HCV vaccine has been developed and the current antiviral regimens have some limitations such as high costs and not being effective in some difficult-to-treat patients.\nProprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease primarily produced in the liver. Its gene expression can be regulated by several transcription factors, such as sterol-regulatory element binding proteins (SREBPs), hepatocyte nuclear factor (HNF)-1, forkhead box O3 (FoxO3) and specificity protein 1 (Sp1). PCSK9 plays an important role in lipid homeostasis through facilitating the degradation of the low-density lipoprotein receptor (LDLR). It also exerts an antiviral effect on HCV. It can suppress HCV entry by reducing HCV receptors LDLR and cluster of differentiation 81. Although PCSK9 has been shown to inhibit HCV replication, the underlying mechanism has not been thoroughly characterized. Besides, the effects of PCSK9 on HCV translation and virion assembly/secretion have not been studied.\nSince PCSK9 can regulate lipid levels and the HCV life cycle is closely connected with lipid metabolism, I hypothesized that PCSK9 has an inhibitory effect on the HCV life cycle. I first showed that PCSK9 does not affect HCV translation or virion assembly/secretion. However, an inhibitory effect of PCSK9 on HCV replication is shown by overexpressing or knocking down PCSK9 in HCV replicon cells. Then I demonstrated that PCSK9-induced LDLR degradation is not involved in HCV replication regulation using gain-of-function (D374Y) or loss-of-function (Δaa. 31-52) PCSK9 mutants for LDLR degradation. Moreover, the auto-cleavage of PCSK9 affects HCV replication since only uncleaved proPCSK9 suppresses HCV replication and cleaved PCSK9 does not have effect on HCV replication. Next, I found that PCSK9 can interact with several HCV proteins including NS5A. The PCSK9 interacting region of NS5A is aa. 95-215 in domain I. The interaction between PCSK9 and NS5A inhibits NS5A dimerization and HCV RNA binding to NS5A. Considering that NS5A dimerization and RNA binding activity of NS5A are required for HCV replication, the interaction between PCSK9 and NS5A could be a mechanism of the inhibitory effect of PCSK9 on HCV replication. \nSince interferon (IFN) produced by innate immune system is important to clear viral infection and PCSK9 can inhibit HCV infection, I further hypothesized that PCSK9 affects HCV infection through regulating IFN production. I showed that PCSK9 suppresses IFNβ expression at the transcription and protein levels. The inhibitory effect of PCSK9 on IFNβ promoter/enhancer activity is mediated by positive regulatory domain IV in the IFNβ enhancer region where the activating transcription factor-2 (ATF-2)/c-Jun complex can bind. I demonstrated an interaction between PCSK9 and ATF-2. This interaction reduces ATF-2/c-Jun dimerization and ATF-2/c-Jun binding to IFNβ enhancer, which could explain how PCSK9 inhibits IFNβ expression. This is a novel function of PCSK9.\nHCV can differently modulate transcription factors involved in PCSK9 expression including SREBPs, HNF-1 and FoxO3, but how HCV regulates PCSK9 expression remains unknown. In this study, I demonstrated that HCV can up-regulate PCSK9 promoter activity in the context of HCV infection and in HCV replicon cells. Among HCV viral proteins, NS2, NS3, NS3-4A, NS5A and NS5B enhance, and p7 or NS4B decreases PCSK9 promoter activity. I also showed that transcription factors SREBP-1c, HNF-1α and Sp1 increase PCSK9 promoter activity in HCV replicon cells, whereas SREBP-1a, HNF-1β and FoxO3 have an inhibitory effect.\nIn conclusion, I showed complex interactions between HCV and PCSK9. On one hand, HCV up-regulates PCSK9 promoter activity. On the other hand, PCSK9 inhibits HCV replication via the interaction with NS5A. It also suppresses IFNβ expression via the interaction with ATF-2, which may regulate HCV infection. This research advances the understanding of the regulation of PCSK9 and the effects of PCSK9 on viral infection and IFN expression, and may help to optimize anti-HCV treatments.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».