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Nucleocapsid proteins: roles beyond viral RNA packaging

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Viral nucleocapsid proteins (NCs) enwrap the RNA genomes of viruses to form NC–RNA complexes, which act as a template and are essential for viral replication and transcription. Beyond packaging viral RNA, NCs also play important roles in virus replication, transcription, assembly, and budding by interacting with viral and host cellular proteins. Additionally, NCs can inhibit interferon signaling response and function in cell stress response, such as inducing apoptosis. Finally, NCs can be the target of vaccines, benefiting from their conserved gene sequences. Here, we summarize important findings regarding the additional functions of NCs as much more than structural RNA‐binding proteins, with specific emphasis on (1) their association with the viral life cycle, (2) their association with host cells, and (3) as ideal candidates for vaccine development. WIREs RNA 2016, 7:213–226. doi: 10.1002/wrna.1326 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Regulation
Nucleocapsid proteins (NCs) package the viral genome RNAs (gRNAs). For RNA viruses, NCs enwrap the viral gRNAs to form NC–RNA complexes, which act as a template for viral replication and transcription. NCs also interact with viral polymerase complexes to form ribonucleoprotein (RNP) to initiate the viral replication and transcription.
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Viral nucleocapsid proteins (NCs) interfere with several stages of innate immune signaling. When RNA viruses infect cells, retinoic acid‐inducible gene I (RIG1) and melanoma differentiation‐associated gene 5 (MDA5) respond to the viral RNA and then activate the adaptor protein located on the mitochondria virus‐induced signaling adapter (VISA), and VISA passes the signal to TANK‐binding kinase 1 (TBK1) and IκB kinase‐related kinase (IKKε), both of which are phosphokinases that can phosphosphorylate IFN‐regulated factor 3 (IRF3) and interferon regulatory factor 7 (IRF7). Finally, phosphorylated IRF3 and IRF7 translocate into the nucleus to activate interferon (IFN) promoter and lead to the production of IFN. Several viral NCs can block the IFN signal transfer; lymphocytic choriomeningitis virus (LCMV) NCs can block the IFN signal transfer through interfere the function of IKKε; NCs of Andes virus (ANDV) and porcine epidemic diarrhea virus (PEDV) inhibit IFN signal by interfering with function of TBK1 and IRF3; Arenavirus NCs prevent IRF3 from localizing to nucleus and Borna diseae virus (BDV) NCs prevent IRF7 from localizing to nucleus.
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Viral nucleocapsid proteins (NCs) function in several stages of the virus life cycle. After virus entry into the cell, inclusion bodies (IBs) were formed to be the center of transcription and replication, and the NC was one of indispensable partners of IBs. NCs package the viral RNA, to protect the viral RNA from digestion by RNase, and together with other viral components into viral particles, which then mature and yield. (a) NC of coronavirus can be phosphorylated by Glycogen synthase kinase‐3 (GSK3), which enhance the interaction of NC and DDX1 to facilitate template switching from discontinuous to continuous transcription for producing longer sgmRNAs and genome RNAs (gRNAs); (b) NCs package the viral RNA and associate with other viral proteins to form viral replication ‘factory’; (c) Hepatitis C virus (HCV) core protein interacts with the μ subunit of clathrin adaptor protein complex 2 (AP2M1) which is phosphorylated by AP2 associated kinase 1 (AAK1) and cyclin G associated kinase (GAK), and dephosphorylated by Phosphatase 2A (PP2A), and phosphorylated AP2M1 helps NC for assembly; diacylglycerol acyltransferase 1 (DGAT1) can recruit core protein to lipid droplets to facilitate the interaction of core with HCV non‐structural protein 5A (NS5A) protein; mitogen‐activated protein kinase‐activated protein kinase 3 (MAPKAPK3) increased HCV internal ribosome entry site (IRES)‐mediated translation and this activity was further enhanced by core protein; (d) NCs interact with M protein and cdE2 to facilitate the viral budding.
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