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FEBS J . Acetylation of the influenza A virus polymerase subunit PA in the N-terminal domain positively regulates its endonuclease activity

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  • FEBS J . Acetylation of the influenza A virus polymerase subunit PA in the N-terminal domain positively regulates its endonuclease activity


    FEBS J


    . 2021 Jul 16.
    doi: 10.1111/febs.16123. Online ahead of print.
    Acetylation of the influenza A virus polymerase subunit PA in the N-terminal domain positively regulates its endonuclease activity


    Dai Hatakeyama 1 , Masaki Shoji 1 , Seiryo Ogata 2 , Takeshi Masuda 2 , Masahiro Nakano 3 , Tsugunori Komatsu 1 , Ayaka Saitoh 1 , Kyoko Makiyama 1 , Hazuki Tsuneishi 1 , Asuka Miyatake 1 , Mizuki Takahira 1 , Erina Nishikawa 1 , Ayana Ohkubo 1 , Takeshi Noda 3 , Yoshihiro Kawaoka 4 5 , Sumio Ohtsuki 2 , Takashi Kuzuhara 1



    Affiliations

    Abstract

    The post-translational acetylation of lysine residues is found in many non-histone proteins and is involved in a wide range of biological processes. Recently, we showed that the nucleoprotein of the influenza A virus is acetylated by histone acetyltransferases (HATs), a phenomenon that affects viral transcription. Here, we report that the PA subunit of influenza A virus RNA-dependent RNA polymerase is acetylated by the HATs, P300/CBP-associated factor (PCAF) and general control non-derepressible 5 (GCN5), resulting in accelerated endonuclease activity. Specifically, the full-length PA subunit expressed in cultured 293T cells was found to be strongly acetylated. Moreover, the partial recombinant protein of the PA N-terminal region containing the endonuclease domain was also acetylated by PCAF and GCN5 in vitro, which facilitated its endonuclease activity. Mass spectrometry analyses identified K19 as a candidate acetylation target in the PA N-terminal region. Notably, the substitution of the lysine residue at position 19 with glutamine, a mimic of the acetyl-lysine residue, enhanced its endonuclease activity in vitro; this point mutation also accelerated influenza A virus RNA-dependent RNA polymerase activity in the cell. Our findings suggest that PA acetylation is important for the regulation of the endonuclease and RNA polymerase activities of the influenza A virus.

    Keywords: RNA polymerase; acetylation; acetyltransferase; endonuclease; influenza virus.

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