Aminoacyl-tRNA Synthetase: A Non-Negligible Molecule in RNA Viral Infection

Figure 1. MSC and EPRS in viral infection. (A) Schematic representation of the MSC, which contains 9 cy-aaRSs and 3 AIMPs. The cartoon model of the MSC was generated based on previous studies [11,12,13]. AIMP, aaRS-interacting multi-functional protein; ArgRS, arginyl-tRNA synthetase; AspRS, aspartyl-tRNA synthetase; EPRS (E-P), glutamyl-prolyl-tRNA synthetase; GluRS, glutamyl-tRNA synthetase; IleRS, isoleucyl-tRNA synthetase; LeuRS, leucyl-tRNA synthetase; LysRS, lysyl-tRNA synthetase; MetRS, methionyl-tRNA synthetase; and MSC, multi-synthetase complex. (B) IFN-γ stimulation induces sequential phosphorylation of EPRS at serine 886 (S886) and S999 (red stars), which results in the dissociation of EPRS from the MSC. The released EPRS forms a GAIT complex with NSAP1, p-L13a, and GAPDH. The GAIT complex further represses translation of inflammatory proteins via its interaction with eIF4G (left). By contrast, influenza A induces EPRS phosphorylation at S990 (red star) and causes its release from the MSC. The released EPRS interacts with PCBP2 and blocks PCBP2-mediated ubiquitination of MAVS. The increase in stabilized MAVS (blue arrow) further suppresses viral replication (right). eIF,…

Figure 2. AIMP1 and TrpRS in viral infection. (A) Upon HCV infection, HCV envelope protein E2 directly interacts with AIMP1 and induces a ubiquitin-dependent proteasomal degradation of AIMP1. On the other hand, HCV E2 leads to the upregulation of GRP78 (blue arrow) but inhibits the interaction between AIMP1 and its stabilizer GRP78, resulting in AIMP1 degradation. The degradation of AIMP1 leads to activation of TGF-β signaling and increased GP96 expression (blue arrow) on cell surface. AIMP1, aaRS-interacting multi-functional protein 1; GP96, heat shock protein GP96; GRP78, glucose regulated protein 78; HCV, hepatitis C virus; and TGF, transforming growth factor. (B) VSV infection induces secretion of TrpRS (purple ball) from immune cells including lymphocytes (left upper cells in dark blue), monocytes (left middle cells in light blue), and macrophages (left lower cells in light purple). The secreted TrpRS elicits innate immune responses and induces antiviral cytokines including IFN-α, IFN-β, IL-6, and TNF-α (particles in different colors). This response is mediated by the TLR4-MD2 receptor on the cell surface. The increased cytokines further induce signaling cascades that result in the…

Figure 3. LysRS in HIV-1 infection. (A) After HIV-1 infection, the RNA genome of HIV-1 is converted to DNA, which is primed by the host cellular tRNALys. Human LysRS is also packaged into HIV-1 virions via the interaction with the viral precursor proteins Gag and GagPol. On the other hand, HIV-1 infection triggers the release of LysRS from the MSC via the phosphorylation of serine 207 (S207) (red star) in LysRS. The released LysRS partially translocates to the nucleus. HIV-1, human immunodeficiency virus type 1; LysRS (K), lysyl-tRNA synthetase; and MSC, multi-synthetase complex. (B) In immunoglobulin E (IgE)-stimulated mast cells, LysRS is phosphorylated at S207, followed by its release from the MSC. The dissociated LysRS further traffics to the nucleus, where it forms a complex with MITF and Hint-1, as well as produces high levels of Ap4A (blue arrow). The interaction between Ap4A and Hint-1 results in the dissociation of Hint-1 from the complex and the activation of MITF-targeted gene transcription. Ap4A, diadenosine tetraphosphate and MITF, microphthalmia transcription factor.

Figure 4. GlyRS and TrpRS in viral infection. (A) Stem-loop domains of PV RNA are numbered by Roman numbers. The PV IRES covers the region from domain II through domain VI. The non-initiator of AUG at 586, the authentic AUG at 743 as well as the polypyrimidine tract are shown. GlyRS (green ball) binds to the domain V of PV IRES, adjacent to the binding site of the eIF4G-eIF4A complex. The upper part of domain V mimics the anticodon stem-loop of tRNAGly with the anticodon ACC. The binding site of the eIF4G-eIF4A complex on domain V is based on a previous study [61]. eIF, eukaryotic initiation factor; GlyRS (G), glycyl-tRNA synthetase; IRES, internal ribosome entry site; and PV, poliovirus. (B) EV-A71 semi- or non-permissive cells have low or no surface expression of TrpRS (purple ball), which decreases EV-A71 infection (red curved arrow, left). By contrast, IFN-γ induces the expression and membrane translocation of TrpRS, which in turn sensitizes cells to viral infection via the direct interaction with EV-A71, ultimately leading to enhanced viral internalization (right). EV-A71, enterovirus A71; IFN, interferon; and TrpRS (W), tryptophanyl-tRNA synthetase.