An 'Arms Race' between the Nonsense-mediated mRNA Decay Pathway and Viral Infections

Abstract

The Nonsense-mediated mRNA Decay (NMD) pathway is an RNA quality control pathway conserved among eukaryotic cells. While historically thought to predominantly recognize transcripts with premature termination codons, it is now known that the NMD pathway plays a variety of roles, from homeostatic events to control of viral pathogens. In this review we highlight the reciprocal interactions between the host NMD pathway and viral pathogens, which have shaped both the host antiviral defense and viral pathogenesis.

Keywords: Anti-viral response; Nonsense-mediated mRNA decay; RNA biology; Viruses.

Fig. 1

A) Schematic of the NMD pathway: Initially, a spliced mRNA has the exon junction complex (EJC) loaded on to the mRNA. This includes the core members: RBM8A, eIF4A3, and MAGOH. When there is a PTC upstream of a retained EJC, UPF2 and UPF3 act as a bridge to recruit the UPF1/SMG1 complex and initiate the NMD pathway. UPF1 is then phosphorylated by SMG1, leading to the recruitment of the decapping and deadenylating complex created by SMG5/SMG7, resulting in exonucleolytic decay. SMG6 is recruited for a separate endonucleolytic decay pathway. In plants, the complex VARICOSE (VCS) is responsible for decapping mRNAs. B) Viral interactors overlaid on the NMD pathway: HTLV Rex and PEMVp62 protects mRNA from degradation by blocking NMD initiation on transcripts. WNV capsid interacts and interferes with RBM8A and MAGOH. HTLV Tax interferes with INT6 and UPF1 function, whereas ZIKV capsid blocks UPF1 function. WNV capsid and HCV core interfere with WIBG recycling of EJC factors. The CaMV TAV protein blocks decapping by interfering with the complex VCS.

Fig. 2

A) Zika Virus (ZIKV), West Nile Virus (WNV) and Hepatitis C Virus (HCV): Flavivirus structural proteins protect viral mRNA. ZIKV and WNV capsid degrade UPF1. HCV core and WNV capsid interact with WIBG to block interaction between WIBG and RBM8A/MAGOH. WNV capsid also relocalizes RBM8A and MAGOH. B) Potato Virus X (PVX) and Pea Enation Mosaic Virus 2 (PEMV2): Elements of the viral mRNA lead to NMD degradation. The 3’UTR contains elements responsible for NMD degradation, where removal of the 3’UTR protects viral RNA from the NMD. PEMV2 p62 interacts with RNA to protect it from degradation. C) Rous Sarcoma Virus (RSV) and Turnip Crinkle Virus (TCV): Elements of the viral mRNA protect from NMD degradation. A segment of the 3’ UTR confers protection to viral mRNAs from the NMD and protect from RNA decay machinery. D) Human T-cell Lymphotropic Virus (HTLV): Two different HTLV proteins protect viral RNA from the NMD pathway. While Rex interaction with viral RNA confers protection, Tax plays a more active role by both inhibiting the ability of UPF1 to interact with RNA and properly translocate across bound RNA molecules. Furthermore, Tax inhibits INT6 interactions with UPF1. E) Human Immunodeficiency Virus (HIV): UPF1 is involved in the RNA export of HIV genomes from the nucleus into the cytoplasm and then loaded into infectious virions. The host protein UPF2 inhibits UPF1 interaction with viral RNA and inhibits viral replication.