Battle between influenza A virus and a newly identified antiviral activity of the PARP-containing ZAPL protein.
Previous studies showed that ZAPL (PARP-13.1) exerts its antiviral activity via its N-terminal zinc fingers that bind the mRNAs of some viruses, leading to mRNA degradation. Here we identify a different antiviral activity of ZAPL that is directed against influenza A virus. This ZAPL antiviral activity involves its C-terminal PARP domain, which binds the viral PB2 and PA polymerase proteins, leading to their proteasomal degradation. After the PB2 and PA proteins are poly(ADP-ribosylated), they are associated with the region of ZAPL that includes both the PARP domain and the adjacent WWE domain that is known to bind poly(ADP-ribose) chains. These ZAPL-associated PB2 and PA proteins are then ubiquitinated, followed by proteasomal degradation. This antiviral activity is counteracted by the viral PB1 polymerase protein, which binds close to the PARP domain and causes PB2 and PA to dissociate from ZAPL and escape degradation, explaining why ZAPL only moderately inhibits influenza A virus replication. Hence influenza A virus has partially won the battle against this newly identified ZAPL antiviral activity. Eliminating PB1 binding to ZAPL would be expected to substantially increase the inhibition of influenza A virus replication, so that the PB1 interface with ZAPL is a potential target for antiviral development.
Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712.
Chien-Hung
CH
Liu
Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712.
Ligang
L
Zhou
Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712.
Guifang
G
Chen
Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712 rkrug@austin.utexas.edu.
Robert M
RM
Krug
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004285:Dogs; D006801:Humans; D047468:Immunoprecipitation; D009980:Influenza A virus / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054875:Ubiquitination; D014764:Viral Proteins / Q000378:metabolism*
D017931:DNA Primers; D018076:DNA, Complementary; D016601:RNA-Binding Proteins; D014764:Viral Proteins; C527496:ZC3HAV1 protein, human; D011065:Poly(ADP-ribose) Polymerases
ZAPL PARP domain; influenza A virus polymerase protein subunits; poly(ADP-ribosylation); proteasomal degradation; ubiquitination