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Similar results were obtained using Huh-7.5.1 cells and parental Huh-7 cells (Figure?S3). Collectively, Ceramidase these results indicate that the ESCRT machinery is required for HCV-infected and SGR cells to activate pDCs, suggesting that MVBs are required for this process and reinforcing the notion that the pDC activating signal is exosomal HCV RNA. Annexin A2 (ANXA2) is an RNA-binding protein (Aukrust et?al., 2007; Filipenko et?al., 2004) that plays a key role in membrane vesicle trafficking and MVB biogenesis (Gerke et?al., 2005; Mayran et?al., 2003; Morel et?al., 2009). Interestingly, recent reports indicated that ANXA2 is recruited to HCV replication sites where it regulates virus particle production (Backes et?al., 2010; Saxena et?al., 2012). Anticancer Compound Library in vitro Therefore, we used shRNA-mediated knockdown to determine whether ANXA2 is required for HCV-infected Huh-7.5.1c2 cells and SGR cells to trigger IFN-�� production by cocultured pDCs. As shown in Figure?7, ANXA2 downregulation in HCV-SGR cells (Figure?7A) abolished their ability to trigger IFN-�� production by cocultured pDCs (Figure?7B) without inhibiting HCV-RNA replication (Figure?7C), the latter confirming the results of Backes et?al. (2010). The ANXA2 requirement for pDC activation was confirmed by the restoration of pDC activation by ANXA2 shRNA-downregulated SGR cells by ectopic overexpression of an ANXA2 encoding shRNA-resistant RNA (Figure?7B). Consistent with these results, downregulation of ANXA2 expression in HCV-infected cells (Figure?7D) decreased their ability to trigger IFN-�� production by cocultured pDCs by >20-fold (Figure?7E) without inhibiting selleck screening library HCV-RNA replication (Figure?7F) or significantly (