8jce | pdb_00008jce
Cryo-EM Structure of Chikungunya Virus Nonstructural Protein 1 with m7GpppAmU
Structural highlights
FunctionPOLN_CHIKS P123 is short-lived polyproteins, accumulating during early stage of infection. It localizes the viral replication complex to the cytoplasmic surface of modified endosomes and lysosomes. By interacting with nsP4, it starts viral genome replication into antigenome. After these early events, P123 is cleaved sequentially into nsP1, nsP2 and nsP3. This sequence of delayed processing would allow correct assembly and membrane association of the RNA polymerase complex (By similarity). nsP1 is a cytoplasmic capping enzyme. This function is necessary since all viral RNAs are synthesized in the cytoplasm, and host capping enzymes are restricted to the nucleus. The enzymatic reaction involves a covalent link between 7-methyl-GMP and nsP1, whereas eukaryotic capping enzymes form a covalent complex only with GMP. nsP1 capping would consist in the following reactions: GTP is first methylated and then forms the m7GMp-nsP1 complex, from which 7-methyl-GMP complex is transferred to the mRNA to create the cap structure. Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces filopodium-like structure formation at the surface of the host cell (By similarity). nsP2 has two separate domain with different biological activities. The N-terminal section is part of the RNA polymerase complex and has RNA trisphosphatase and RNA helicase activity. The C-terminal section harbors a protease that specifically cleaves and releases the four mature proteins (By similarity). Also inhibits cellular transcription by inducing rapid degradation of POLR2A, a catalytic subunit of the RNAPII complex. The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response. nsP3 is essential for minus strand and subgenomic 26S mRNA synthesis (By similarity). nsP4 is an RNA dependent RNA polymerase. It replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a 26S subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This 26S mRNA codes for structural proteins (By similarity). Publication Abstract from PubMedChikungunya virus (CHIKV) non-structural 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 m(7)GMP from a variety of capped RNA substrates including host mRNAs. We then provide the structural basis of this function with a high-resolution cryogenic-electron microscopy structure of nsP1 in complex with the unconventional cap-1 substrate RNA m(7)GpppA(m)U. We show that the 5'ppRNA species generated by decapping can trigger RIG-I-mediated interferon (IFN) 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. Chikungunya virus Non-structural Protein 1 is a versatile RNA capping and decapping enzyme.,Law MCY, Zhang K, Tan YB, Nguyen TM, Luo D J Biol Chem. 2023 Oct 31:105415. doi: 10.1016/j.jbc.2023.105415. PMID:37918803[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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