RESUMEN
The life cycle of hepatitis C virus (HCV) is highly dependent on host proteins for virus propagation. By transcriptome sequencing analysis, we identified host genes that were highly differentially expressed in HCV-infected cells. Of these candidates, we selected Death receptor 6 (DR6) for further characterization. DR6 is an orphan member of the tumor necrosis factor receptor superfamily. In the present study, we demonstrated that both mRNA and protein levels of DR6 were increased in the context of HCV replication. We further showed that promoter activity of DR6 was increased by HCV infection. By employing promoter-linked reporter assay, we showed that HCV upregulated DR6 via ROS-mediated NF-κB pathway. Both mRNA and protein levels of DR6 were increased by NS4B or NS5A. However, NS5A but not NS4B specifically interacted with DR6. We showed that HCV modulated JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner. Interestingly, Akt signaling cascade was regulated by protein interplay between DR6 and NS5A. Silencing of DR6 expression resulted in decrease of infectious HCV production without affecting viral entry, replication, and translation. Together, these data indicate that HCV modulates DR6 signaling pathway for viral propagation and may contribute to HCV-mediated pathogenesis.
Asunto(s)
Hepacivirus/patogenicidad , Hepatitis C/virología , Interacciones Huésped-Patógeno/fisiología , Receptores del Factor de Necrosis Tumoral/metabolismo , Línea Celular , Hepacivirus/fisiología , Hepatitis C/metabolismo , Humanos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Regulación hacia Arriba , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Internalización del Virus , Replicación Viral , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: The intracompartmental septum in the first extensor compartment in patients with de Quervain's disease has been associated with disease development and prognosis. However, with the exception of surgical exploration, there is no way of detecting the septum. QUESTIONS/PURPOSES: We evaluated the accuracy of sonography for identifying the intracompartmental septum in the first extensor compartment in patients with de Quervain's disease using surgical findings as the reference standard. PATIENTS AND METHODS: We performed surgical release of the first extensor compartment in 43 wrists of 40 patients who were unresponsive to nonoperative treatment. In each case, a sonographic evaluation was performed before surgery by a radiologist and the sonographic and surgical findings were compared. RESULTS: Sonography identified the intracompartmental septum in 19 of the 19 septum-present wrists and absence of the septum in 23 of the 24 septum-absent wrists. The sensitivity of sonography was 100% (95% confidence interval, 80%-100%), its specificity 96% (95% confidence interval, 78%-100%), accuracy 98% (95% confidence interval, 87%-100%), positive predictive value 95% (95% confidence interval, 74%-100%), and negative predictive value 100% (95% confidence interval, 83%-100%). Sonography also identified septum-like structures in 15 of 37 (41%) asymptomatic contralateral wrists. CONCLUSIONS: Sonography is useful for detecting the intracompartmental septum in the first extensor compartment in patients with de Quervain's disease. LEVEL OF EVIDENCE: Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.