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Bacterial Artificial Chromosomes: A Functional Genomics Tool for the Study of Positive-strand RNA Viruses
Published on: December 29, 2015
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Chikungunya virus nonstructural protein 1 is a versatile RNA capping and decapping enzyme
Michelle Cheok Yien Law1, Kuo Zhang1, Yaw Bia Tan1
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
The Journal of Biological Chemistry
|November 2, 2023
Summary
Chikungunya virus nsP1 protein can remove RNA caps, triggering antiviral responses. This decapping activity is conserved in alphaviruses and may aid viral gene expression.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Chikungunya virus (CHIKV) nonstructural protein 1 (nsP1) possesses methyltransferase and guanylyltransferase activities essential for viral RNA 5' end cap formation.
- Understanding nsP1's catalytic functions and interactions with host systems is crucial for comprehending CHIKV pathogenesis.
Purpose of the Study:
- To investigate the catalytic versatility of CHIKV nsP1 beyond cap synthesis.
- To elucidate the structural mechanisms underlying nsP1's novel RNA-modifying activities.
- To explore the implications of nsP1's function in virus-host immune interactions.
Main Methods:
- Purification of recombinant CHIKV nsP1.
- Biochemical assays to assess decapping activity on various capped RNA substrates.
- High-resolution cryo-electron microscopy (cryo-EM) to determine the structure of nsP1 bound to an RNA substrate.
- Analysis of the impact of 5'ppRNA species on the retinoic acid-inducible gene I (RIG-I) pathway.
Main Results:
- CHIKV nsP1 demonstrated the ability to reverse guanylyl transfer, removing m7GMP from capped RNAs, including host mRNAs.
- A high-resolution cryo-EM structure revealed nsP1 complexed with a cap-1 RNA substrate (m7GpppAmU), providing structural insights into its function.
- The decapping activity generated 5'ppRNA species that activated the RIG-I-mediated interferon response.
- This decapping activity was found to be conserved across other alphaviral nsP1 proteins.
Conclusions:
- Alphaviruses, including CHIKV, possess a novel mechanism involving nsP1-mediated RNA decapping to activate antiviral immunity.
- This activity may contribute to viral gene expression by promoting cellular mRNA degradation, analogous to influenza virus cap-snatching.
- The findings reveal a new facet of alphavirus-host interaction and potential therapeutic targets.
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