Yellow fever virus capsid protein is a potent suppressor of RNA silencing that binds double-stranded RNA

Abstract

Mosquito-borne flaviviruses, including yellow fever virus (YFV), Zika virus (ZIKV), and West Nile virus (WNV), profoundly affect human health. The successful transmission of these viruses to a human host depends on the pathogen's ability to overcome a potentially sterilizing immune response in the vector mosquito. Similar to other invertebrate animals and plants, the mosquito's RNA silencing pathway comprises its primary antiviral defense. Although a diverse range of plant and insect viruses has been found to encode suppressors of RNA silencing, the mechanisms by which flaviviruses antagonize antiviral small RNA pathways in disease vectors are unknown. Here we describe a viral suppressor of RNA silencing (VSR) encoded by the prototype flavivirus, YFV. We show that the YFV capsid (YFC) protein inhibits RNA silencing in the mosquito Aedes aegypti by interfering with Dicer. This VSR activity appears to be broadly conserved in the C proteins of other medically important flaviviruses, including that of ZIKV. These results suggest that a molecular "arms race" between vector and pathogen underlies the continued existence of flaviviruses in nature.

Slicing and dicing viruses: antiviral RNA interference in mammals

“…Expression of influenza virus NS1, vaccinia virus E3L, reovirus σ3 and Nodamura virus (NoV) B2 proteins inhibits RNAi in plants and/or insect cells (Lichner et al, ; Bucher et al, ; Delgadillo et al, ; Li et al, ). In mammalian cells, a plethora of mammalian virus‐encoded VSRs, including primate foamy virus type 1 (PFV‐1) Tas, NoV B2, HCV core, IAV NS1, HIV Tat, Ebola VP35, VP30 and VP40, CoV N, SARS‐CoV 7a, YFV capsid, DENV NS4B, human enterovirus 71 (HEV 71) 3A and adenovirus virus‐associated RNA I (VA1), can reduce shRNA/siRNA‐mediated knockdown of reporter genes (Table ) (Lu & Cullen, ; Andersson et al, ; Lecellier et al, ; Sullivan & Ganem, ; Wang et al, ; Haasnoot et al, ; Chen et al, ; de Vries et al, ; Karjee et al, ; Fabozzi et al, ; Kakumani et al, ; Cui et al, ; Samuel et al, ; Qiu et al, ). Most viral proteins identified thus far that display VSR activity share the ability to bind dsRNA and mutations that affect their dsRNA‐binding domain block VSR activity, arguing that their principal mode of action is sequestration of dsRNA from Dicer (Table ).…”

Structural disorder in the proteome and interactome of Alkhurma virus (ALKV)

“…The C protein can migrate to the nucleus of flavivirus-infected cells [97] and modulate functions of host nuclear proteins [94], e.g., acting as a histone mimic, interacting with core histones, and disrupting nucleosome formation [98], or interacting with other host nuclear proteins, such as heterogeneous nuclear ribonucleoprotein K (hnRNP-K) [99], death domain-associated protein 6 (DAXX) [100], and nucleolin (NCL) [101]. Finally, the C protein can be involved in the inhibition of the RNA silencing via interference with the host ribonuclease Dicer [102].…”

Midgut barriers prevent the replication and dissemination of the yellow fever vaccine inAedes aegypti

“…Interestingly, Myles and colleagues recently showed that the YFV C protein counteracts the RNA interference pathway in Ae. aegypti by protecting double-stranded viral RNA from Dicer-2-induced cleavage [50]. No amino acid sequence responsible for this effect has been identified.…”

“…This unique mutation and/or these differences in C protein diversity could modulate their RNA interference suppression activities. It is unfortunate that Myles and colleagues [50] did not provide information on the viral strain they used.…”