title: Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses.
abstract: Enterovirus 71 (EV71) is a positive-stranded RNA virus which is capable of inhibiting innate immunity. Among virus-encoded proteins, the 3C protein compromises the type I interferon (IFN-I) response mediated by retinoid acid-inducible gene-I (RIG-I) or Toll-like receptor 3 that activates interferon regulatory 3 (IRF3) and IRF7. In the present study, we report that enterovirus 71 downregulates IRF7 through the 3C protein, which inhibits the function of IRF7. When expressed in mammalian cells, the 3C protein mediates cleavage of IRF7 rather than that of IRF3. This process is insensitive to inhibitors of caspase, proteasome, lysosome, and autophagy. H40D substitution in the 3C active site abolishes its activity, whereas R84Q or V154S substitution in the RNA binding motif has no effect. Furthermore, 3C-mediated cleavage occurs at the Q189-S190 junction within the constitutive activation domain of IRF7, resulting in two cleaved IRF7 fragments that are incapable of activating IFN expression. Ectopic expression of wild-type IRF7 limits EV71 replication. On the other hand, expression of the amino-terminal domain of IRF7 enhances EV71 infection, which correlates with its ability to interact with and inhibit IRF3. These results suggest that control of IRF7 by the 3C protein may represent a viral mechanism to escape cellular responses.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Lei
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Xue
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
mesh_terms: D000086042:3C Viral Proteases; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D029821:Enterovirus A, Human / Q000201:enzymology / Q000472:pathogenicity*; D006801:Humans; D006868:Hydrolysis; D057131:Immune Evasion; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050839:Interferon Regulatory Factor-7; D050505:Mutant Proteins; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases