Fated for decay: RNA elements targeted by viral endonucleases

Abstract

For over a decade, studies of messenger RNA regulation have revealed an unprecedented level of connectivity between the RNA pool and global gene expression. These connections are underpinned by a vast array of RNA elements that coordinate RNA-protein and RNA-RNA interactions, each directing mRNA fate from transcription to translation. Consequently, viruses have evolved an arsenal of strategies to target these RNA features and ultimately take control of the pathways they influence, and these strategies contribute to the global shutdown of the host gene expression machinery known as "Host Shutoff". This takeover of the host cell is mechanistically orchestrated by a number of non-homologous virally encoded endoribonucleases. Recent large-scale screens estimate that over 70 % of the host transcriptome is decimated by the expression of these viral nucleases. While this takeover strategy seems extraordinarily well conserved, each viral endonuclease has evolved to target distinct mRNA elements. Herein, we will explore each of these RNA structures/sequence features that render messenger RNA susceptible or resistant to viral endonuclease cleavage. By further understanding these targeting and escape mechanisms we will continue to unravel untold depths of cellular RNA regulation that further underscores the integral relationship between RNA fate and the fate of the cell.

Keywords: RNA decay; RNA element; host-shutoff; targeting; viral endonuclease.

Fig. 1

Messenger RNA features that direct viral endonuclease and decapping enzymes targeting or escape from cleavage. (A) Vaccinia virus (VacV) D9/D10 and African swine flu virus (ASFV) ASFV-DP preferentially cleave mRNA at the site of the 5′ M₇G cap. (B) Herpes simplex virus-1 (HSV-1) vhs recognizes the cap binding complex to facilitate upstream internal cleavage. (C) Coronavirus (CoV) nsp1 indirectly triggers mRNA decay by inactivation of the 40S ribosomal subunit. (D) Influenza A virus (IAV) PA-X preferentially targets and internally cleaves intron-bearing pre-mRNA in the nucleus, coordinating with the host spliceosome and 3′ end processing factors. (E) Kaposi’s sarcoma-associated Herpesvirus (KSHV) SOX internally cleaves mRNA at specific sites. A combination of specific RNA secondary structure and nucleotide sequence directly contribute to SOX target selectivity and cleavage efficiency. (F) RNA elements in the 3′ UTRs of select mRNA have been implicated in facilitating escape from viral endonuclease cleavage.