Flavivirus xrRNAs

Exoribonuclease-Resistant RNAs (xrRNAs) are present across all genera of the Flaviviridae, including mosquito, tick-borne, and no-known vector flaviviruses, as well as pegiviruses, hepaciviruses and pestiviruses[1][2]. Most flaviviruses contain two xrRNAs (xrRNA1 and xrRNA2) near the start of the 3′ untranslated region (UTR), also referred to as SL II and SL IV. Each xrRNA folds into a double pseudoknot (PK) centered around a three-way junction (3WJ), forming a protective ring structure around the 5’ end that physically blocks 5′→3′ exonuclease progression[3][4][5][6]. Many xrRNAs contain an additional short stem-loop (SL) downstream of the second PK, which is nonessential for resistance. Based on structural differences, flavivirus xrRNAs are classified into subclasses 1a, 1b, and 2. The subgenomic RNAs (called sfRNA1 and sfRNA2) derived from exoribonuclease stalling in front of xrRNA1 and xrRNA2, respectively, contribute to immune evasion and viral pathogenicity in both mammalian and insect hosts[7], although their precise molecular mechanisms remain incompletely understood.

References

  1. ^ Szucs, Matthew J.; Nichols, Parker J.; Jones, Rachel A.; Vicens, Quentin; Kieft, Jeffrey S. (29 September 2020). "A New Subclass of Exoribonuclease-Resistant RNA Found in Multiple Genera of Flaviviridae". mBio. 11 (5): e02352–20. doi:10.1128/mBio.02352-20. ISSN 2150-7511. PMC 7527734. PMID 32994331.
  2. ^ Dilweg, Ivar W.; Savina, Anya; Köthe, Susanne; Gultyaev, Alexander P.; Bredenbeek, Peter J.; Olsthoorn, René C. L. (December 2021). "All genera of Flaviviridae host a conserved Xrn1-resistant RNA motif". RNA biology. 18 (12): 2321–2329. doi:10.1080/15476286.2021.1907044. ISSN 1555-8584. PMC 8632102. PMID 33858294.
  3. ^ Chapman, Erich G.; Costantino, David A.; Rabe, Jennifer L.; Moon, Stephanie L.; Wilusz, Jeffrey; Nix, Jay C.; Kieft, Jeffrey S. (18 April 2014). "The structural basis of pathogenic subgenomic flavivirus RNA (sfRNA) production". Science (New York, N.Y.). 344 (6181): 307–310. doi:10.1126/science.1250897. ISSN 1095-9203. PMC 4163914. PMID 24744377.
  4. ^ Akiyama, Benjamin M.; Laurence, Hannah M.; Massey, Aaron R.; Costantino, David A.; Xie, Xuping; Yang, Yujiao; Shi, Pei-Yong; Nix, Jay C.; Beckham, J. David; Kieft, Jeffrey S. (2 December 2016). "Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease". Science (New York, N.Y.). 354 (6316): 1148–1152. doi:10.1126/science.aah3963. ISSN 1095-9203. PMC 5476369. PMID 27934765.
  5. ^ Jones, Rachel A.; Steckelberg, Anna-Lena; Vicens, Quentin; Szucs, Matthew J.; Akiyama, Benjamin M.; Kieft, Jeffrey S. (2021). "Different tertiary interactions create the same important 3D features in a distinct flavivirus xrRNA". RNA (New York, N.Y.). 27 (1): 54–65. doi:10.1261/rna.077065.120. ISSN 1469-9001. PMC 7749634. PMID 33004436.
  6. ^ Langeberg, Conner J.; Szucs, Matthew J.; Sherlock, Madeline E.; Vicens, Quentin; Kieft, Jeffrey S. (15 May 2025). "Tick-borne flavivirus exoribonuclease-resistant RNAs contain a double loop structure". Nature Communications. 16 (1): 4515. doi:10.1038/s41467-025-59657-7. ISSN 2041-1723. PMC 12081666. PMID 40374626.
  7. ^ Slonchak, Andrii; Khromykh, Alexander A. (2018). "Subgenomic flaviviral RNAs: What do we know after the first decade of research". Antiviral Research. 159: 13–25. doi:10.1016/j.antiviral.2018.09.006. ISSN 1872-9096. PMID 30217649.

General Flavivirus exoribonuclease-resistant RNA element in Rfam

Tick-borne Flavivirus exoribonuclease-resistant RNA element in Rfam

Insect-specific Flavivirus exoribonuclease-resistant RNA element in Rfam

No-known vector Flavivirus exoribonuclease-resistant RNA element in Rfam

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