The Stress Granule Component TIA-1 Binds Tick-Borne Encephalitis Virus RNA and Is Recruited to Perinuclear Sites of Viral Replication To Inhibit Viral Translation

Abstract

Flaviviruses are a major cause of disease in humans and animals worldwide. Tick-borne encephalitis virus (TBEV) is the most important arthropod-borne flavivirus endemic in Europe and is the etiological agent of tick-borne encephalitis, a potentially fatal infection of the central nervous system. However, the contributions of host proteins during TBEV infection are poorly understood. In this work, we investigate the cellular protein TIA-1 and its cognate factor TIAR, which are stress-induced RNA

Functions of the 3′ and 5′ genome RNA regions of members of the genus Flavivirus

“…Cell proteins binding to the genome 3′ NCR and/or to a viral replication complex protein may function to facilitate the initiation of minus strand viral RNA synthesis. A number of different cell proteins have been reported to bind to a 3′ NCR flavivirus probe including La, PTB, PABP, NF-9 FBP1, DDX5, eEF1A, TIAR/TIA-1 (De Nova-Ocampo, Villegas-Sepulveda et al 2002, Polacek, Friebe et al 2009, Chien, Liao et al 2011, Gomila, Martin et al 2011, Li, Ge et al 2013, Albornoz, Carletti et al 2014) but the region of the 3′ NCR to which these proteins bound was not mapped and some of these proteins also bound to additional flavivirus RNA terminal sequences (De Nova-Ocampo, Villegas-Sepulveda et al 2002, Yocupicio-Monroy, Padmanabhan et al 2007, Li, Ge et al 2014) as well as to some of the viral proteins (Li, Ge et al 2013, Li, Ge et al 2014). Additional studies identified cell proteins binding to particular regions within the flavivirus 3′ NCR.…”

“…Binding of TIA-1 to the 3′ NCR of tick borne encephalitis virus negatively affects genome translation (Albornoz, Carletti et al 2014). Both DDX5 and DDX3 have been reported to bind to both the 3′ NCR and the 5′ NCR and to positively regulate genome translation (Li, Ge et al 2014).…”

Visual detection of Flavivirus RNA in living cells

“…By positioning the MS2 RNA binding sites in antisense orientation we originally hoped to be able to track also (À)RNA. The extra-vesicular compartment is connected to the cytosol and accessible to proteins such as MS2-EYFP or TIA-1/TIAR, which bind the viral RNA to regulate viral translation and shuttle between the extra-vesicular compartment and stress granules (SG) [114]. Since the (À)RNA template is much less abundant than the replicated (+) RNA, the MS2-EYFP signal would be either too small to be visible above background or not accessible to MS2, either being protected by the replication complex or being present only in a doublestranded conformation.…”

T-cell intracellular antigens in health and disease

“…Under conditions of stress, the a subunit of the translation initiation factor Eukaryotic translation initiation factor 2 (eIF2) is phosphorylated, principally at serine 51, by a family of kinases that includes Eukaryotic translation initiation factor 2-a kinase 1 (HRI), Eukaryotic translation initiation factor 2-a kinase 2 (PKR), Eukaryotic translation initiation factor 2-a kinase 3 (PERK) and Eukaryotic translation initiation factor 2-a kinase 4 (GCN2), depending of the types of stresses and cellular lines involved. [34][35][36][37][38][39][40][41][42] This phosphorylation abolishes the ability of eIF2B to exchange GDP for GTP, which results in a decrease in the levels of eIF2-GTP-tRNAMet ternary complex. In turn, this leads to incorrect formation of the translation pre-initiation complexes.…”

“…34,35 These inactive translation pre-initiation complexes associated with mRNAs accumulate in the cytoplasm and, due to the aggregation properties of the Q domain of TIA and Poly (AC) binding protein (PABP) proteins, bind among themselves (self-aggregate), creating large foci of mRNA and protein known as stress granules (SG). [36][37] SG formation favors cell survival in stress conditions, such as starvation or limitations in amino acid availability, oxidative or osmotic stress, etc., as well as pathophysiological situations, as for instance viral infection 37 and Alzheimer disease. 38 In these adverse conditions, the cell enters a cellular biology resting state, inhibiting translation in general and allowing energy to be saved for repair of the damage caused by the stressful insult.…”