原文摘要：
Like other enteroviruses, EV71 relies on phosphatidylinositol-4-kinase IIIβ (PI4KB) for genome RNA replication. However, how PI4KB is recruited to the genome replication sites of EV71 remains elusive. Recently, we reported that a host factor ACBD3 is needed for EV71 replication by interacting with viral 3A protein. Here, we show that ACBD3 is required for the recruitment of PI4KB to RNA replication sites. Overexpression of viral 3A or EV71 infection stimulates the interaction of PI4KB and ACBD3. Consistently, EV71 infection induces the production of phosphatidylinositol-4-phosphate (PI4P). Furthermore, PI4KB, ACBD3 and 3A are all localized to the viral RNA replication sites. Accordingly, PI4KB or ACBD3 depletion by siRNA leads to a reduction in the PI4P production after EV71 infection. I44A or H54Y substitution in 3A interrupts the stimulation of PI4KB and ACBD3. Further analysis suggests that stimulation of ACBD3-PI4KB interaction is also important for the replication of enterovirus 68 but disadvantageous to human rhinovirus 16. These results reveal a mechanism of enterovirus replication that involves a selective strategy for recruitment of PI4KB to the RNA replication sites.
IMPORTANCE Enterovirus 71, like other human enteroviruses, replicates its genome within host cells, where viral proteins efficiently utilize cellular machineries. While multiple factors are involved, it is largely unclear how viral replication is controlled. We show that the 3A protein of enterovirus 71 recruits an enzyme phosphatidylinositol-4-kinase IIIβ by interacting with ACBD3, which alter cellular membranes through the production of a lipid PI4P. Consequently, the viral and host proteins form a large complex that is necessary for RNA synthesis at replication sites. Notably, PI4KB-ACBD3 interaction also differentially mediates the replication of enterovirus 68 and rhinovirus 16. These results provide a new insight into the molecular network of enterovirus replication.
附第1篇论文信息：
Title：Enterovirus 71 inhibits pyroptosis through cleavage of GSDMD
Author：Xiaobo Lei, Zhenzhen Zhang, Xia Xiao, Jianli Qi, Bin He* and Jianwei Wang*
Abstract：Enterovirus 71 (EV71) can cause hand, foot, and mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remain poorly understand. Here, we report that EV71 induces degradation of GSDMD, an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1-193. However, unlike the N-terminal fragment produced by casaspe-1 cleavage, this fragment fails to trigger cell death or inhibits EV71 replication. Importantly, T239D or F240D substitution abrogates the activity of GSDMD composed of amino acids 1-275. This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response.
Importance：Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated IL-1β secretion. In this process, the N-terminal domain p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection down-regulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N—terminal fragment disrupted for inducing cell pyroptosis. Notably, the 1-275aa fragment (p30) inhibits EV71 replication whereas the 1-193aa fragment does not. These results reveal a new strategy for EV71 to evade the antiviral response.
DOI：10.1128/JVI.01069-17
原文链接：http://jvi.asm.org/content/early/2017/06/29/JVI.01069-17.abstract