Abstract
The mRNA 5' cap structure serves both to protect transcripts from degradation and promote their translation. Cap removal is thus an integral component of mRNA turnover that is carried out by cellular decapping enzymes, whose activity is tightly regulated and coupled to other stages of the mRNA decay pathway. The poxvirus vaccinia virus (VACV) encodes its own decapping enzymes, D9 and D10, that act on cellular and viral mRNA, but may be regulated differently than their cellular counterparts. Here, we evaluated the targeting potential of these viral enzymes using RNA sequencing from cells infected with wild-type and decapping mutant versions of VACV as well as in uninfected cells expressing D10. We found that D9 and D10 target an overlapping subset of viral transcripts but that D10 plays a dominant role in depleting the vast majority of human transcripts, although not in an indiscriminate manner. Unexpectedly, the splicing architecture of a gene influences how robustly its corresponding transcript is targeted by D10, as transcripts derived from intronless genes are less susceptible to enzymatic decapping by D10. As all VACV genes are intronless, preferential decapping of transcripts from intron-containing genes provides an unanticipated mechanism for the virus to disproportionately deplete host transcripts and remodel the infected cell transcriptome.
Highlights
The gene expression pathways for the vast majority of DNA viruses mimic those of the host cell, and they often rely on host machinery found in the nucleus for transcription, mRNA processing and splicing
Vaccinia virus (VACV) is a DNA virus of the poxviridae family that was used as a vaccine for immunization against smallpox, enabling eradication of the smallpox virus
Unusual for DNA viruses, poxviruses like vaccinia virus (VACV) replicate in the cytoplasm and must encode their own DNA replication and RNA processing machinery
Summary
The gene expression pathways for the vast majority of DNA viruses mimic those of the host cell, and they often rely on host machinery found in the nucleus for transcription, mRNA processing and splicing. A notable exception are the poxviruses such as vaccinia virus (VACV), which are unusual as DNA viruses because they replicate in the cytoplasm and do not have access to the cellular mRNA synthesis and processing factors located in the nucleus [1]. This includes splicing factors, and in contrast to the majority of mammalian genes, all VACV genes are intronless. VACV encodes two decapping enzymes, D9 and D10, that remove the protective 5’ cap on host and viral transcripts, leading to degradation of the decapped mRNAs by cellular exonucleases such as XRN1 [5,6]. Decapping-induced degradation of host transcripts may further benefit the virus by increasing ribosome availability for viral translation
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