Chikungunya virus nonstructural protein 1 is a versatile RNA capping and decapping enzyme

• Main Authors: Law, Michelle Cheok Yien, Zhang, Kuo, Tan, Yaw Bia, Nguyen, Trinh Mai, Luo, Dahai
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2024
• Subjects: Science::Medicine; mRNA; Positive-Sense RNA Virus
• Online Access: https://hdl.handle.net/10356/173042
• Institution: Nanyang Technological University

Chikungunya virus (CHIKV) nonstructural protein 1 (nsP1) contains both the N7-guanine methyltransferase and guanylyltransferase activities and catalyzes the 5' end cap formation of viral RNAs. To further understand its catalytic activity and role in virus-host interaction, we demonstrate that purified recombinant CHIKV nsP1 can reverse the guanylyl transfer reaction and remove the m7GMP from a variety of capped RNA substrates including host mRNAs. We then provide the structural basis of this function with a high-resolution cryo-EM structure of nsP1 in complex with the unconventional cap-1 substrate RNA m7GpppAmU. We show that the 5'ppRNA species generated by decapping can trigger retinoic acid-inducible gene I-mediated interferon response. We further demonstrate that the decapping activity is conserved among the alphaviral nsP1s. To our knowledge, this is a new mechanism through which alphaviruses activate the antiviral immune response. This decapping activity could promote cellular mRNA degradation and facilitate viral gene expression, which is functionally analogous to the cap-snatching mechanism by influenza virus.