Shiftless inhibits flavivirus replication in vitro and is neuroprotective in a mouse model of Zika virus pathogenesis

Abstract

Flaviviruses such as Zika virus and West Nile virus have the potential to cause severe neuropathology if they invade the central nervous system. The type I interferon response is well characterized as contributing to control of flavivirus-induced neuropathogenesis. However, the interferon-stimulated gene (ISG) effectors that confer these neuroprotective effects are less well studied. Here, we used an ISG expression screen to identify Shiftless (SHFL, C19orf66) as a potent inhibitor of diverse positive-stranded RNA viruses, including multiple members of the Flaviviridae (Zika, West Nile, dengue, yellow fever, and hepatitis C viruses). In cultured cells, SHFL functions as a viral RNA-binding protein that inhibits viral replication at a step after primary translation of the incoming genome. The murine ortholog, Shfl, is expressed constitutively in multiple tissues, including the central nervous system. In a mouse model of Zika virus infection, Shfl−/− knockout mice exhibit reduced survival, exacerbated neuropathological outcomes, and increased viral replication in the brain and spinal cord. These studies demonstrate that Shfl is an important antiviral effector that contributes to host protection from Zika virus infection and virus-induced neuropathological disease.

Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during KSHV lytic replication

“…in 2016, C19ORF66 (here referred to as SHFL), has emerged as a critical piece of the innate immune response to viral infection. SHFL restricts the replication of a vast assortment of DNA, RNA, and retroviruses to varying degrees and is itself an Interferon Stimulated Gene (ISG) ( 20,27 ). Fascinatingly, for each virus that SHFL restricts, a different mechanism has been described.…”

“…SHFL is an interferon stimulated gene (ISG) that is demonstrably a vital piece of the innate immune response to viral infection, capable of suppressing the replication of multiple DNA, RNA, and retroviruses (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Studies of SHFL function over the past 5 years have revealed its multifaceted capacity to negatively modulate viral RNA stability, viral gene translation, and even viral protein stability through interactions with cellular co-factors that coordinate these processes such as cytoplasmic poly(A) binding protein 1 (PABPC1), La Ribonucleoprotein Domain Family Member 1 (LARP1) and the RNA helicase MOV10 (19,20).…”

Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection

“…In nearly every context, this protein was identified as a broad-spectrum anti-viral factor whose expression is upregulated in response to Type I interferon (IFN) induction and generally viral infection. From these studies, several unique identifiers have been attributed to the C19orf66 gene product including FLJ11286 (genomic location), Repressor of Yield of Dengue Virus (RyDEN), Suppressor of Viral Activity-1 (SVA-1), Interferon Regulated Anti-Viral gene (IRAV), and more recently Shiftless (SFL/SHFL) with SHFL finally approved for its official gene symbol [10][11][12][13][14][15][16][17][18][19][20]. SHFL expression can often vary dramatically between cell types as demonstrated by Balinsky and colleagues [11].…”

“…Excitingly, Hanners and colleagues recently studied the in vivo efficacy of SHFL and broadly addressed its capacity to restrict a wide range of positive and negative sense RNA viruses [16]. In previous screens Hanners and colleagues utilized large lentiviral libraries of ISG to identify ISG with strong anti-viral activity against the flavivirus West Nile Virus (WNV), measuring WNV infectivity for each ISG tested.…”

“…An increasing number of large-scale screens have independently identified SHFL as both an anti-viral factor and downstream effector of the Type I, II, and III interferon response to viral infection [2][3][4][5][6][7][8][9]. Some studies have gone even further to characterize SHFL as a potent, broad-spectrum restriction factor for a growing list of DNA, RNA, and Retroviruses (Summarized in Table 1) [8,[10][11][12][13][14][15][16][17][18][19][20]. Many ISGs have evolved to target viral gene expression as it is often the primary battleground that nearly every viral replication steps depend upon.…”