Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun, Di; Chen, Shun; Cheng, Anchun; Wang, Mingshu

During EV71 infection, the expression of IFN-β, tumor necrosis factor (TNF-N), and IFN-stimulated gene 54(ISG54) is inhibited. Among EV71 proteins, 3C pro blocks the virus-induced activation of IFN-β by targeting the cytosolic helicase I RIG-I. However, 3C pro exerts no inhibitory activity against IFN-β promoter activation, which is mediated by MDA5 in EV71 infection [92] . Enteroviral 2A pro proteolytically targets MDA5 and MAVS to block the expression of IFN-I [103] . Notably, members of picornavirus family modulate MDA5 and RIG-I differently. RV and echovirus target RIG-I, whereas PV and EMCV mediate RIG-I and MDA5 [104] [105] [106] . Subsequent studies have revealed that EV71 3C pro induces TRIF cleavage to inhibit NF-κB and IFN-β promoter activation in a caspase-independent manner ( Figure 6 ) [107] . The use of 3C pro mutants has shown that the Q312-S313 junction within TRIF might be a preferred cleavage site [104] . With regard to the constitutive activation domain of IRF7, EV71 3C pro mediates cleavage of IRF7, rather than IRF3, at the Q189-S190 junction when expressed in mammalian cells (Table 4 ) [108] . EV71 3C pro also inhibits NF-κB via cleavage of the transforming growth factor-β-activated kinase 1 (TAK1) and TAB2 complex [109] . The type I IFN antiviral response is closely related to the JAK-STAT signaling pathway, consisting of Janus kinase (JAK) family members and the signal transducers and activators of transcription (STAT) family. EV71 inhibits the type I IFN response through another mechanism of JAK1 downregulation. However, roles for the viral proteinases 2A pro and 3C pro as antagonists have been ruled out [110] . Recently, it has been shown that the PARP9-DTX3L complex which is formed by poly (ADP-ribose) polymerase PARP9 and the DTX3L E3 ubiquitin ligase, can promote STAT1-mediated ISG expression and can induce viral 3C pro degradation [111] . These observations provide guidance for studies of interferon signaling and viral infection. The mechanisms by which picornaviruses inhibit cellular type I IFN and the strategies by which host cells adopt a defense system are complicated.