Abstract
Enterovirus 71 (EV71) is the major causative pathogen of hand, foot, and mouth disease. The lack of understanding of the virus’s pathogenesis hinders the development of anti-virus drugs and the control of EV71 infection. Our previous studies have demonstrated that both mitochondria and endoplasmic reticulum (ER) were altered significantly in EV71 infected cells, but the mechanism is still unclear. In this study, we investigated the effects of EV71 infection on the expression of INF2, a key regulator factor in ER-Mitochondria communication and mitochondrial fission. We found that INF2 was cleaved in EV71 infected RD cells. The INF2 cleavage occurred at Aspartic 1,051 of INF2 and is mediated by activated caspases, predominantly by activated caspase-2. The subcellular localization of INF2 and caspase-2 was significantly altered in infected cells. We speculate that caspase-2-mediated INF2 cleavage is involved in forming viral replication organelles (ROs) and is a positive feedback regulatory mechanism of mitochondrial disorders caused by EV71 infection.
Highlights
Enterovirus71 (EV71), which belongs to the Enterovirus genus of the Picornaviridae family, is the causative agent of hand, foot, and mouth disease (HFMD) and is especially the major cause of severe HFMD (Solomon et al, 2010)
In RD cells transfected with Inverted formin 2 (INF2)-Flag, cleavage fragments could be detected with a molecular weight of about 38 kDa using Flag antibody (Figure 1C), while in RD cells transfected with GFP-INF2, the cleavage fragments could be detected with a molecular weight of about 160 kDa by GFP antibody (Figure 1D)
The results showed that both Enterovirus 71 (EV71)-induced caspase-2 activation and INF2 cleavage were weakened in the cells treated with MitoTEMPO, as evidenced by the decreased intensity of cleavage fragments of INF2 and caspase-2 (Figure 7F), indicating that caspase-2 mediated INF2 cleavage is a positive feedback regulatory mechanism of EV71-induced mitochondrial damage (Figure 8)
Summary
Enterovirus (EV71), which belongs to the Enterovirus genus of the Picornaviridae family, is the causative agent of hand, foot, and mouth disease (HFMD) and is especially the major cause of severe HFMD (Solomon et al, 2010). Acute EV71 infection can lead to severe neurological manifestations and occasionally cause permanent paralysis or death. In China, in 2008, the EV71 infection caused a serious HFMD epidemic in Fuyang City, Anhui Province. The frequency and severity of HFMD have shown an increased annual trend and pose a serious threat to children’s health (Zhang et al, 2010). The mechanisms underlying EV71 pathogenesis are unclear, and a lack of understanding of its viral pathogenesis does not allow the development of drugs against this virus and the control of EV71 infection (Solomon et al, 2010). Further research is needed to elucidate the pathogenesis of EV71
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