Department of Molecular Microbiology, School of Biotechnology, Madurai Kamaraj University, Madurai – 625 021, India.
Research Article
World Journal of Advanced Research and Reviews, 2022, 15(03), 425–442
Article DOI: 10.30574/wjarr.2022.15.3.0944
Received on 16 August 2022; revised on 21 September 2022; accepted on 23 September 2022
RNA polymerases of human influenza viruses A, B and C do not have a capping enzyme, as other RNA viruses, to cap their mRNAs for translation in the host cells. So, they employ a unique ‘cap-snatching’ mechanism, where the mRNA cap structures are snatched from the host cell mRNAs and used as a primer to initiate its own mRNA synthesis. One of the RNA polymerase subunits, the polymerase basic protein subunit 2 (PB2), is shown to involve in the ‘cap-snatching’ mechanism. The active sites for the ‘cap-snatching’ and endonuclease by the PB2 were analyzed by multiple sequence alignment (MSA) analysis and corroborated with the results available from biochemical, site-directed mutagenesis (SDM) and X-ray crystallographic techniques. It is found that the PB2 subunit in all three human influenza viruses habours both the cap-binding motif (CBM) and a HNH/N type endonuclease domain. The CBM is aromatic amino acid rich and the HNH/N is a –DH- based endonuclease in influenza viruses A and C and a –DQ- based one in influenza virus B. The invariant H is proposed to act as a general base to initiate catalysis and the invariant first N is implicated in nucleotide binding. In addition, the nuclear localization signals were also identified in all three human influenza viruses. By sequence similarity, similar HNH/N domain are found in the RNA cleaving CRISPR-Cas13a/13b and CRISPR-Cas12a endoribonucleases. The identification of HNH/N domain in all three human influenza viruses suggests that the PB2 subunit itself could cleave the cap structures from the host cell mRNAs, which are subsequently used as primers to initiate viral mRNA synthesis. These results will facilitate the optimization of endonuclease inhibitors as potential new anti-influenza drugs, and could also help in developing new drugs for flu treatments in the future.
Human influenza viruses; RNA Polymerase basic protein subunit 2; HNH endonuclease; Cap-snatching; CRISPR-Cas13a endoribonuclease; CRISPR-Cas12a endoribonuclease.
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Peramachi Palanivelu. Identification of HNH endonuclease domain in the basic protein 2 subunit of the polymerase of human influenza viruses. World Journal of Advanced Research and Reviews, 2022, 15(3), 425-442. Article DOI: https://doi.org/10.30574/wjarr.2022.15.3.0944