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Complete genome sequences of two novel dicistroviruses detected in yellow crazy ants (Anoplolepis gracilipes)

Lee CC, Lin CY, Hsu HW, Yang CS

Arch Virol, 2020 Nov;165(11):2715-2719.
PMID: 32776255 DOI: 10.1007/s00705-020-04769-2

We report two novel RNA viruses from yellow crazy ants, (Anoplolepis gracilipes) detected using next-generation sequencing. The complete genome sequences of the two viruses were 10,662 and 8,238 nucleotides in length, respectively, with both possessing two open reading frames with three conserved protein domains. The genome organization is characteristic of members of the genus Triatovirus in the family Dicistroviridae. The two novel viruses were tentatively named "Anoplolepis gracilipes virus 1" and "Anoplolepis gracilipes virus 2" (AgrV-1 and AgrV-2). Phylogenetic analyses based on amino acid sequences of the non-structural polyprotein (ORF1) suggest that the two viruses are triatovirus-like viruses. This is the first report on the discovery of novel triatovirus-like viruses in yellow crazy ants with a description of their genome structure (two ORFs and conserved domains of RNA helicase, RNA-dependent RNA polymerase, and capsid protein), complete sequences, and viral prevalence across the Asia-Pacific region.

Matched MeSH terms: RNA Helicases/genetics
Fulltext No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Easton DF, Lesueur F, Decker B, Michailidou K, Li J, Allen J, et al.

J Med Genet, 2016 May;53(5):298-309.
PMID: 26921362 DOI: 10.1136/jmedgenet-2015-103529

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.
METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.
RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).
CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Matched MeSH terms: RNA Helicases/genetics*
Degradation of MicroRNA miR-466d-3p by Japanese Encephalitis Virus NS3 Facilitates Viral Replication and Interleukin-1β Expression

Jiang H, Bai L, Ji L, Bai Z, Su J, Qin T, et al.

J Virol, 2020 07 16;94(15).
PMID: 32461319 DOI: 10.1128/JVI.00294-20

Japanese encephalitis virus (JEV) infection alters microRNA (miRNA) expression in the central nervous system (CNS). However, the mechanism contributing to miRNA regulation in the CNS is not known. We discovered global degradation of mature miRNA in mouse brains and neuroblastoma (NA) cells after JEV infection. Integrative analysis of miRNAs and mRNAs suggested that several significantly downregulated miRNAs and their targeted mRNAs were clustered into an inflammation pathway. Transfection with miRNA 466d-3p (miR-466d-3p) decreased interleukin-1β (IL-1β) expression and inhibited JEV replication in NA cells. However, miR-466d-3p expression increased after JEV infection in the presence of cycloheximide, indicating that viral protein expression reduced miR-466d-3p expression. We generated all the JEV coding proteins and demonstrated NS3 helicase protein to be a potent miRNA suppressor. The NS3 proteins of Zika virus, West Nile virus, and dengue virus serotype 1 (DENV-1) and DENV-2 also decreased miR-466d-3p expression. Results from helicase-blocking assays and in vitro unwinding assays demonstrated that NS3 could unwind pre-miR-466d and induce miRNA dysfunction. Computational models and an RNA immunoprecipitation assay revealed arginine-rich domains of NS3 to be crucial for pre-miRNA binding and degradation of host miRNAs. Importantly, site-directed mutagenesis of conserved residues in NS3 revealed that R226G and R202W reduced the binding affinity and degradation of pre-miR-466d. These results expand the function of flavivirus helicases beyond unwinding duplex RNA to degrade pre-miRNAs. Hence, we revealed a new mechanism for NS3 in regulating miRNA pathways and promoting neuroinflammation.IMPORTANCE Host miRNAs have been reported to regulate JEV-induced inflammation in the CNS. We found that JEV infection could reduce expression of host miRNA. The helicase region of the NS3 protein bound specifically to miRNA precursors and could lead to incorrect unwinding of miRNA precursors, thereby reducing the expression of mature miRNAs. This observation led to two major findings. First, our results suggested that JEV NS3 protein induced miR-466d-3p degradation, which promoted IL-1β expression and JEV replication. Second, arginine molecules on NS3 were the main miRNA-binding sites, because we demonstrated that miRNA degradation was abolished if arginines at R226 and R202 were mutated. Our study provides new insights into the molecular mechanism of JEV and reveals several amino acid sites that could be mutated for a JEV vaccine.

Matched MeSH terms: RNA Helicases/genetics
Rational discovery of dengue type 2 non-competitive inhibitors

Heh CH, Othman R, Buckle MJ, Sharifuddin Y, Yusof R, Rahman NA

Chem Biol Drug Des, 2013 Jul;82(1):1-11.
PMID: 23421589 DOI: 10.1111/cbdd.12122

Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target, and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13 341 small compounds, with the backbone structures of chalcone, flavanone, and flavone, available in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top-ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared with the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents.

Matched MeSH terms: RNA Helicases/genetics