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1.
Nat Commun ; 12(1): 6918, 2021 11 25.
Article in English | MEDLINE | ID: mdl-34824277

ABSTRACT

While viral replication processes are largely understood, comparably little is known on cellular mechanisms degrading viral RNA. Some viral RNAs bear a 5'-triphosphate (PPP-) group that impairs degradation by the canonical 5'-3' degradation pathway. Here we show that the Nudix hydrolase 2 (NUDT2) trims viral PPP-RNA into monophosphorylated (P)-RNA, which serves as a substrate for the 5'-3' exonuclease XRN1. NUDT2 removes 5'-phosphates from PPP-RNA in an RNA sequence- and overhang-independent manner and its ablation in cells increases growth of PPP-RNA viruses, suggesting an involvement in antiviral immunity. NUDT2 is highly homologous to bacterial RNA pyrophosphatase H (RppH), a protein involved in the metabolism of bacterial mRNA, which is 5'-tri- or diphosphorylated. Our results show a conserved function between bacterial RppH and mammalian NUDT2, indicating that the function may have adapted from a protein responsible for RNA turnover in bacteria into a protein involved in the immune defense in mammals.


Subject(s)
Phosphoric Monoester Hydrolases/genetics , Phosphoric Monoester Hydrolases/metabolism , RNA Stability , RNA, Viral/metabolism , Adaptation, Physiological , Animals , Antiviral Agents , Bone Marrow Cells , CRISPR-Cas Systems , Exonucleases , Exoribonucleases , Female , Gene Knockout Techniques , HEK293 Cells , HeLa Cells , Humans , Immunity, Innate , Male , Mice , Mice, Inbred C57BL , Microtubule-Associated Proteins , Polyphosphates , RNA, Bacterial , RNA, Messenger , Virus Replication
2.
Viruses ; 13(2)2021 02 14.
Article in English | MEDLINE | ID: mdl-33672966

ABSTRACT

Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins-a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.


Subject(s)
Adenovirus Infections, Human/metabolism , Adenoviruses, Human/metabolism , Heparitin Sulfate/metabolism , Receptors, Virus/metabolism , Adenovirus Infections, Human/virology , Adenoviruses, Human/chemistry , Adenoviruses, Human/genetics , Capsid Proteins/chemistry , Capsid Proteins/genetics , Capsid Proteins/metabolism , Child, Preschool , Female , Humans , Infant , Male , Protein Domains
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