Biology:Exoribonuclease-resistant RNA
Exoribonuclease-resistant RNAs (xrRNAs) are structured viral RNA elements that block 5′→3′ degradation by host exoribonucleases such as Xrn1. This resistance leads to the accumulation of stable subgenomic RNA fragments that play key roles in viral replication and pathogenicity.[1][2] First identified in the flavivirus West Nile virus (WNV),[3] xrRNAs are now known across diverse RNA viruses infecting vertebrates, insects, and plants.[4][5][6]
xrRNAs in the Flaviviridae Family
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.[5][6] 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[7][8][9][10] 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,[1] although their precise molecular mechanisms remain incompletely understood.
References
- ↑ 1.0 1.1 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.
- ↑ Vicens, Quentin; Kieft, Jeffrey S. (2021). "Shared properties and singularities of exoribonuclease-resistant RNAs in viruses". Computational and Structural Biotechnology Journal 19: 4373–4380. doi:10.1016/j.csbj.2021.07.024. ISSN 2001-0370. PMID 34471487.
- ↑ Pijlman, Gorben P.; Funk, Anneke; Kondratieva, Natasha; Leung, Jason; Torres, Shessy; van der Aa, Lieke; Liu, Wen Jun; Palmenberg, Ann C. et al. (2008-12-11). "A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity". Cell Host & Microbe 4 (6): 579–591. doi:10.1016/j.chom.2008.10.007. ISSN 1934-6069. PMID 19064258.
- ↑ Steckelberg, Anna-Lena; Vicens, Quentin; Kieft, Jeffrey S. (2018-12-18). "Exoribonuclease-Resistant RNAs Exist within both Coding and Noncoding Subgenomic RNAs". mBio 9 (6): e02461–18. doi:10.1128/mBio.02461-18. ISSN 2150-7511. PMID 30563900.
- ↑ 5.0 5.1 Szucs, Matthew J.; Nichols, Parker J.; Jones, Rachel A.; Vicens, Quentin; Kieft, Jeffrey S. (2020-09-29). "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. PMID 32994331.
- ↑ 6.0 6.1 Dilweg, Ivar W.; Savina, Anya; Köthe, Susanne; Gultyaev, Alexander P.; Bredenbeek, Peter J.; Olsthoorn, René C. L. (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. PMID 33858294.
- ↑ Chapman, Erich G.; Costantino, David A.; Rabe, Jennifer L.; Moon, Stephanie L.; Wilusz, Jeffrey; Nix, Jay C.; Kieft, Jeffrey S. (2014-04-18). "The structural basis of pathogenic subgenomic flavivirus RNA (sfRNA) production". Science 344 (6181): 307–310. doi:10.1126/science.1250897. ISSN 1095-9203. PMID 24744377. Bibcode: 2014Sci...344..307C.
- ↑ Akiyama, Benjamin M.; Laurence, Hannah M.; Massey, Aaron R.; Costantino, David A.; Xie, Xuping; Yang, Yujiao; Shi, Pei-Yong; Nix, Jay C. et al. (2016-12-02). "Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease". Science 354 (6316): 1148–1152. doi:10.1126/science.aah3963. ISSN 1095-9203. PMID 27934765. Bibcode: 2016Sci...354.1148A.
- ↑ 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 27 (1): 54–65. doi:10.1261/rna.077065.120. ISSN 1469-9001. PMID 33004436.
- ↑ Langeberg, Conner J.; Szucs, Matthew J.; Sherlock, Madeline E.; Vicens, Quentin; Kieft, Jeffrey S. (2025-05-15). "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. PMID 40374626. Bibcode: 2025NatCo..16.4515L.
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