The Restrictome of Flaviviruses

Abstract

Flaviviruses are a genus of mostly arthropod-borne RNA viruses that cause a range of pathologies in humans. Basic knowledge on flaviviruses is rapidly expanding, partly due to their status as frequent emerging or re-emerging pathogens. Flaviviruses include the dengue, Zika, West Nile, tick-borne encephalitis and yellow fever viruses (DENV, ZIKV, WNV, TBEV and YFV, respectively). As is the case with other families of viruses, the success of productive infection of human cells by flaviviruses depends in part on the antiviral activity of a heterogeneous group of cellular antiviral proteins called restriction factors. Restriction factors are the effector proteins of the cell-autonomous innate response against viruses, an immune pathway that also includes virus sensors as well as intracellular and extracellular signal mediators such as type I interferons (IFN-I). In this review, I summarize recent progress toward the identification and characterization of flavivirus restriction factors. In particular, I focus on IFI6, Schlafen 11, FMRP, OAS-RNase L, RyDEN, members of the TRIM family of proteins (TRIM5α, TRIM19, TRIM56, TRIM69 and TRIM79α) and a new mechanism of action proposed for viperin. Recent and future studies on this topic will lead to a more complete picture of the flavivirus restrictome, defined as the ensemble of cellular factors with demonstrated anti-flaviviral activity.

Keywords: Flavivirus; Innate immunity; Interferon; Restriction factor; TRIM proteins.

Fig. 1

Schematic representation of early flavivirus infection stages affected by selected IFN-I-inducible restriction factors. Blue arrows and numbers represent essential viral infection steps, as follows: (1) flavivirus particle attachment to its specific receptor, followed by endocytosis-mediated entry; (2) fusion accompanied with uncoating of the viral core; (3) establishment of replication organelles at the endoplasmic reticulum, where both genome replication and gene expression occur; (4) early translation of the incoming viral genome, generating the viral enzymes necessary to viral replication, such as the protease NS2B/NS3 and the RNA polymerase NS5; (5) viral genome replication through double-stranded intermediates; (6) late viral translation, which yields the structural proteins for the subsequent assembly of novel viral particles (not shown). Black text boxes and arrows show restriction factors and pathways. IFITM2/3 interfere with fusion and uncoating. IFI6 prevents the establishment of replication organelles, thus disrupting viral RNA replication. TRIM56 and RyDEN bind to the viral RNA, affecting RNA replication. OAS proteins activate RNaseL upon binding to double-stranded RNA replication intermediates, resulting in the digestion of both viral and cellular RNAs. Viperin promotes the formation of a nucleotide analog, ddhCTP, resulting in the inhibition of the NS5-mediated genome replication. NS5 is targeted to a lysosomal degradation pathway by TRIM79α. The viral NS2B/NS3 protease is targeted to a proteasomal degradation pathway by TRIM5α, TRIM69 as well as Viperin. FMRP inhibits viral gene-translating ribosomes. Finally, Slfn11 reduces the levels of key tRNAs, hence inhibiting viral gene translation. This schematic view does not take into account virus-specific, host species-specific and cellular context-specific limitations to the restriction pathways shown.