Virus-induced translational arrest through 4EBP1/2-dependent decay of 5′-TOP mRNAs restricts viral infection

Abstract

The mosquito-transmitted bunyavirus, Rift Valley fever virus (RVFV), is a highly successful pathogen for which there are no vaccines or therapeutics. Translational arrest is a common antiviral strategy used by hosts. In response, RVFV inhibits two well-known antiviral pathways that attenuate translation during infection, PKR and type I IFN signaling. Despite this, translational arrest occurs during RVFV infection by unknown mechanisms. Here, we find that RVFV infection triggers the decay of core translation machinery mRNAs that possess a 5′-terminal oligopyrimidine (5′-TOP) motif in their 5′-UTR, including mRNAs encoding ribosomal proteins, which leads to a decrease in overall ribosomal protein levels. We find that the RNA decapping enzyme NUDT16 selectively degrades 5′-TOP mRNAs during RVFV infection and this decay is triggered in response to mTOR attenuation via the translational repressor 4EBP1/2 axis. Translational arrest of 5′-TOPs via 4EBP1/2 restricts RVFV replication, and this increased RNA decay results in the loss of visible RNA granules, including P bodies and stress granules. Because RVFV capsnatches in RNA granules, the increased level of 5′-TOP mRNAs in this compartment leads to snatching of these targets, which are translationally suppressed during infection. Therefore, translation of RVFV mRNAs is compromised by multiple mechanisms during infection. Together, these data present a previously unknown mechanism for translational shutdown in response to viral infection and identify mTOR attenuation as a potential therapeutic avenue against bunyaviral infection.translational arrest | 5′-TOP mRNA | RNA decay | Rift Valley fever virus |

A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation

“…2D; Moy et al 2014b). An endogenous mRNA, hDCP2 (the levels of which are unaffected by RVFV infection) (Hopkins et al 2015), was not significantly bound. Similar results were found for SINV infection, in which SINV genomic and subgenomic RNAs (which function as mRNAs) were significantly bound by hZCCHC7 (Fig.…”

“…RNASEL, which is induced by interferon signaling, nonspecifically degrades both viral and cellular RNA as a step toward cell death (Hassel et al 1993;Castelli et al 1997;Brennan-Laun et al 2014). In contrast, recent studies have shown that 5 ′ exonucleases and decapping machinery selectively target flaviviruses and bunyaviruses, respectively (Hopkins et al 2013(Hopkins et al , 2015Moon and Wilusz 2013). The 3 ′ -to-5 ′ RNA exosome and its associated cofactor complexes have been implicated in some immune functions but are less understood.…”

Tuning innate immunity by translation

“…Additionally, mRNAs that contain 5 -terminal oligopyrimidine tracts (5 TOP) are preferentially translated during bacterial infection to support the high synthesis of pro-inflammatory cytokines [23]. In contrast, viral infection (e.g., mosquito-transmitted bunya virus, Rift Valley fever virus) leads to reduced translation of 5 TOP mRNAs upon mTOR-dependent 4E-BP phosphorylation [24]. Viruses snatch the cap-structure including the 5 TOP to enhance translation of their own mRNAs [25].…”

“…Viruses snatch the cap-structure including the 5 TOP to enhance translation of their own mRNAs [25]. The cell counteracts the viral propagation by preferential degradation of mRNAs bearing 5 TOP motifs [24]. Notably, proteins participating in the translation machinery (e.g.…”

“…ribosomal proteins, translation factors) also bear 5 TOP motifs. 5 TOP mRNA degradation reduces the amount of the translation machinery components together with newly 5 TOP-decorated viral mRNA which consequently represses viral replication [24]. However, various pathogens elicit different reactions: Rift Valley fever virus infection reduces activated protein kinase B (PKB or Akt) activity in a TLR-dependent fashion and down-regulates 5 TOP mRNA translation, whereas the increased translation during microbial infection appears to be conferred by ILreceptor activity [23,24].…”