Flavivirus 5' UTR

Flavivirus 5' UTR are untranslated regions in the genome of viruses in the genus Flavivirus.

Flavivirus-5UTR
Consensus secondary structure and sequence conservation of Flavivirus 5' UTR
Identifiers
SymbolFlavivirus-5UTR
RfamRF03546
Other data
RNA typeCis-reg
GOGO:0039694
SOSO:0000205
PDB structuresPDBe

Background

The Flavivirus positive-oriented, single-stranded RNA genome has a length of 10,000 - 11,000 bases. The genus includes human pathogens like Zika virus, West-Nile virus, Dengue virus, Yellow Fever virus and other.[1]

The 5' UTR of flaviviruses are highly structured, has a length of approximately 100 nucleotides and harbors two conserved RNA secondary structures which are vital for the viral life cycle.[2][3] During replication, the 5' UTR interacts with the 3' UTR of the genome to initiate synthesis of new viral replicates and viral protein translation. In direct adjacency to the 5' UTR lies the cHP structure, which is essential for the viral replication.[4][5]

5'SLA

The first structural element is termed 5'SLA and comprises three stems (S1, S2, S3) folded as L-shaped-like stem structure,[6] and a side structure domain (SSD). Its overall length is around 70 nucleotides. Disruption experiments of S1 and S2 led to a stop of viral replication. Further, SLA is the promoter for RNA synthesis and interacts with the viral protein NS5 during circularization of the viral genome.[7][8] After recruitment of NS5, the two loop regions of S3 (TL) and SSD (SSL) are considered to interact with NS5 to promote polymerase activity.[4][9] Despite the diversity of SSD, its stable structure is essential for infectivity.[4]

5'SLB

The second element is termed 5'SLB and contains the translation initiation codon at the top region of the stem loop. It further contains the 5'UAR (upstream AUG region), which is essential for the circularization of the genome.[10] The 5'UAR interacts with the 3'UAR, which is located at the 3' UTR of the genome to form a long-range RNA-RNA interaction.[10]

cHP

The capsid-coding hairpin region (cHP) actually lies in the ORF of the viral genome and is followed by the 5'CS (conserved sequence), which forms another long-range RNA-RNA interaction with the 3' UTR (3'CS).[5] The cHP aids in the start codon recognition and viral replication. Studies show that the function of cHP is sequence-independent but structure-dependent.[11]

References
  1. "International Committee on Taxonomy of Viruses (ICTV)". talk.ictvonline.org. Retrieved 2020-08-14.
  2. Ng, Wy; Soto-Acosta, Ruben; Bradrick, Shelton; Garcia-Blanco, Mariano; Ooi, Eng (2017-06-06). "The 5′ and 3′ Untranslated Regions of the Flaviviral Genome". Viruses. 9 (6): 137. doi:10.3390/v9060137. ISSN 1999-4915. PMC 5490814. PMID 28587300.
  3. Gebhard, Leopoldo G.; Filomatori, Claudia V.; Gamarnik, Andrea V. (2011-09-15). "Functional RNA Elements in the Dengue Virus Genome". Viruses. 3 (9): 1739–1756. doi:10.3390/v3091739. ISSN 1999-4915. PMC 3187688. PMID 21994804.
  4. Zeng, Miao; Duan, Yanping; Zhang, Wei; Wang, Mingshu; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Zhao, Xinxin; Yang, Qiao; Wu, Ying; Zhang, Shaqiu (2020-03-27). "Universal RNA Secondary Structure Insight Into Mosquito-Borne Flavivirus (MBFV) cis-Acting RNA Biology". Frontiers in Microbiology. 11: 473. doi:10.3389/fmicb.2020.00473. ISSN 1664-302X. PMC 7118588. PMID 32292394.
  5. Clyde, Karen; Barrera, Julio; Harris, Eva (2008-09-01). "The capsid-coding region hairpin element (cHP) is a critical determinant of dengue virus and West Nile virus RNA synthesis". Virology. 379 (2): 314–323. doi:10.1016/j.virol.2008.06.034. PMC 2628549. PMID 18676000.
  6. Lee, Eunhye; Bujalowski, Paul J.; Teramoto, Tadahisa; Gottipati, Keerthi; Scott, Seth D.; Padmanabhan, Radhakrishnan; Choi, Kyung H. (2021-05-05). "Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase". Nature Communications. 12 (1): 2530. Bibcode:2021NatCo..12.2530L. doi:10.1038/s41467-021-22846-1. ISSN 2041-1723. PMC 8100141. PMID 33953197.
  7. Filomatori, C. V. (2006-08-15). "A 5' RNA element promotes dengue virus RNA synthesis on a circular genome". Genes & Development. 20 (16): 2238–2249. doi:10.1101/gad.1444206. ISSN 0890-9369. PMC 1553207. PMID 16882970.
  8. Yu, Li; Nomaguchi, Masako; Padmanabhan, R.; Markoff, Lewis (2008-04-01). "Specific requirements for elements of the 5′ and 3′ terminal regions in flavivirus RNA synthesis and viral replication". Virology. 374 (1): 170–185. doi:10.1016/j.virol.2007.12.035. PMC 3368002. PMID 18234265.
  9. Filomatori, Claudia V.; Iglesias, Nestor G.; Villordo, Sergio M.; Alvarez, Diego E.; Gamarnik, Andrea V. (2011-03-04). "RNA Sequences and Structures Required for the Recruitment and Activity of the Dengue Virus Polymerase". Journal of Biological Chemistry. 286 (9): 6929–6939. doi:10.1074/jbc.M110.162289. ISSN 0021-9258. PMC 3044948. PMID 21183683.
  10. Alvarez, Diego E.; Lodeiro, María F.; Ludueña, Silvio J.; Pietrasanta, Lía I.; Gamarnik, Andrea V. (2005-06-01). "Long-Range RNA-RNA Interactions Circularize the Dengue Virus Genome". Journal of Virology. 79 (11): 6631–6643. doi:10.1128/JVI.79.11.6631-6643.2005. ISSN 0022-538X. PMC 1112138. PMID 15890901.
  11. Clyde, Karen; Harris, Eva (2006-03-01). "RNA Secondary Structure in the Coding Region of Dengue Virus Type 2 Directs Translation Start Codon Selection and Is Required for Viral Replication". Journal of Virology. 80 (5): 2170–2182. doi:10.1128/JVI.80.5.2170-2182.2006. ISSN 0022-538X. PMC 1395379. PMID 16474125.
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