A poxvirus decapping enzyme localizes to mitochondria to regulate RNA metabolism and translation, and promote viral replication Institutional Repository Document uri icon

abstract

  • AbstractDecapping enzymes remove the 5-cap of eukaryotic mRNA, leading to accelerated RNA decay. They are critical in regulating RNA homeostasis and play essential roles in many cellular and life processes. They are encoded in many organisms and viruses, including vaccinia virus, which was used as the vaccine to eradicate smallpox. Vaccinia virus encodes two decapping enzymes, D9 and D10, that are necessary for efficient viral replication and pathogenesis. However, the underlying molecular mechanism regulating vaccinia decapping enzymes function is still largely elusive. Here we demonstrated that vaccinia D10 localized almost exclusively to mitochondria that are highly mobile cellular organelles, providing an innovative mechanism to concentrate D10 locally and mobilize it to efficiently decap mRNAs. As mitochondria were barely present in viral factories, where viral transcripts are produced, suggesting that mitochondrial localization provides a spatial mechanism to preferentially decap cellular mRNAs over viral mRNAs. We identified three amino acids responsible for D10s mitochondrial localization. Loss of mitochondrial localization significantly impaired viral replication, reduced D10s ability to resolve RNA 5-cap aggregation during infection, diminished D10s gene expression shutoff and mRNA translation promotion abilities.ImportanceDecapping enzymes comprise many members from various organisms ranging from plants, animals, and viruses. The mechanisms regulating their functions vary and are still largely unknown. Our study provides the first mitochondria-localized decapping enzyme, D10, encoded by vaccinia virus that was used as the vaccine to eradicate smallpox. Loss of mitochondrial localization significantly impaired viral replication and D10s gene expression shutoff and mRNA translation promotion ability. Mitochondrial localization is a spatial mechanism to concentrate D10 locally and mobilize it to efficiently and preferentially target cellular mRNAs for decapping and promote viral mRNA translation. Our results have broad impacts on understanding the functions and mechanisms of decapping enzymes.

altmetric score

  • 6.65

author list (cited authors)

  • Cao, S., Molina, J. A., Cantu, F., Hernandez, C., & Yang, Z.

citation count

  • 2

complete list of authors

  • Cao, Shuai||Molina, Joshua A||Cantu, Fernando||Hernandez, Candy||Yang, Zhilong

Book Title

  • bioRxiv

publication date

  • October 2021