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Peer-reviewedCC BY-NC 4.0Nucleic Acids Research

Functional roles for viral RNA ribosylation in mammalian cells

  • John D Sears1
  • Che-Kang Chang1
  • Takayoshi Shirasaki1
  • Paul Sylvester2
  • Rebekah Dickmander1
  • Nicholas A Saba1
  • Wes Sanders1
  • Mark T Heise1,2
  • Nathaniel J Moorman1,3
  1. 1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 ,
  2. 2Department of Genetics, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 ,
  3. 3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 ,
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Abstract

In mammalian cells, the addition of ADP-ribose to proteins and DNA plays well established roles in regulating cell function. Recently, RNA ribosylation was also found in mammalian cells under conditions of cell stress, though the functional consequences remain unclear. Here we find that infection with chikungunya virus, a positive strand RNA virus that causes frequent widespread epidemics, increases overall levels of RNA ribosylation in human fibroblasts. During infection, viral RNA is ribosylated by the PARP12 ribosyltransferase, which is counteracted by the viral nsP3 ribosylhydrolase. Increased viral RNA ribosylation resulted in decreased translation in cell-free systems and infected fibroblasts, and more rapid viral RNA decay. Further, ribosylated RNA potently induced the expression of antiviral host response genes. Together these data show the first functional consequences of RNA ribosylation in mammalian cells by showing that RNA ribosylation inhibits translation, decreases RNA stability, and creates a novel pathogen-associated molecular pattern that activates the host innate immune response. As macrodomains are present in multiple unrelated viruses, our data suggest RNA ribosylation is a novel component of cellular antiviral sensing pathway. These results define a framework for understanding how RNA ribosylation regulates RNA metabolism during viral infection.

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Cite

BibTeXRIS
BibTeX
@article{sears2026functional,
  title = {{Functional roles for viral RNA ribosylation in mammalian cells}},
  author = {John D Sears and Che-Kang Chang and Takayoshi Shirasaki and Paul Sylvester and Rebekah Dickmander and Nicholas A Saba and Wes Sanders and Mark T Heise and Nathaniel J Moorman},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag918},
  url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag918/8863813},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Functional roles for viral RNA ribosylation in mammalian cells
AU  - John D Sears
AU  - Che-Kang Chang
AU  - Takayoshi Shirasaki
AU  - Paul Sylvester
AU  - Rebekah Dickmander
AU  - Nicholas A Saba
AU  - Wes Sanders
AU  - Mark T Heise
AU  - Nathaniel J Moorman
PY  - 2026
DA  - 2026/10/05
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag918
UR  - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag918/8863813
AB  - In mammalian cells, the addition of ADP-ribose to proteins and DNA plays well established roles in regulating cell function. Recently, RNA ribosylation was also found in mammalian cells under conditions of cell stress, though the functional consequences remain unclear. Here we find that infection with chikungunya virus, a positive strand RNA virus that causes frequent widespread epidemics, increases overall levels of RNA ribosylation in human fibroblasts. During infection, viral RNA is ribosylated by the PARP12 ribosyltransferase, which is counteracted by the viral nsP3 ribosylhydrolase. Increased viral RNA ribosylation resulted in decreased translation in cell-free systems and infected fibroblasts, and more rapid viral RNA decay. Further, ribosylated RNA potently induced the expression of antiviral host response genes. Together these data show the first functional consequences of RNA ribosylation in mammalian cells by showing that RNA ribosylation inhibits translation, decreases RNA stability, and creates a novel pathogen-associated molecular pattern that activates the host innate immune response. As macrodomains are present in multiple unrelated viruses, our data suggest RNA ribosylation is a novel component of cellular antiviral sensing pathway. These results define a framework for understanding how RNA ribosylation regulates RNA metabolism during viral infection.
SN  - 0305-1048
SN  - 1362-4962
ER  -