eIF5A is activated by virus infection or dsRNA and facilitates virus replication through modulation of interferon production

Abstract

Active hypusine-modified initiation elongation factor 5A is critical for cell proliferation and differentiation, embryonic development, and innate immune response of macrophages to bacterial infection. Here, we demonstrate that both virus infection and double-stranded RNA viral mimic stimulation induce the hypusination of eIF5A. Furthermore, we show that activation of eIF5A is essential for the replication of several RNA viruses including influenza A virus, vesicular stomatitis virus, chikungunya virus, mayaro virus, una virus, zika virus, and punta toro virus. Finally, our data reveal that inhibition of eIF5A hypusination using the spermidine analog GC7 or siRNA-mediated downmodulation of eIF5A1 induce upregulation of endoplasmic reticulum stress marker proteins and trigger the transcriptional induction of interferon and interferon-stimulated genes, mechanisms that may explain the broad-spectrum antiviral activity of eIF5A inhibition.

Comparative RNA-seq analysis of resistant and susceptible banana genotypes reveals molecular mechanisms in response to banana bunchy top virus (BBTV) infection

“…Expression of translation elongation factor eEF1A (Ma10_g13420) and eukaryotic translation initiation factor eIF5A (Ma11_g09120) were likewise increased by ~ 1.4-fold and ~ 2.6-fold, respectively, most possibly, in response to the invading virus. Being a critical step for successful viral replication, subversion of the host’s protein synthesis machinery and increasing the expression of the components, such as the eEF1A and eIF5A, are needed by the viral pathogen 29 , 30 . Genes involved in RNA biosynthesis and processing such as RNA polymerase sigma factor 70 (Ma11_g15590), phosphorolytic exoribonuclease PNP (Ma10_g20770) were also up-regulated in the susceptible variety, signifying their potential involvement in BBTV replication.…”

Spermidine suppresses DC activation via eIF5A hypusination and metabolic adaptation

“…Regulating or mimicking metabolites within specific immune cells is an ongoing area of research that offers a potential strategy for treating autoimmune diseases 21 but is unclear in DCs whether immunosuppression is induced directly via hypusination or indirectly via increased mitochondrial respiration. Certain RNA viruses, including influenza, directly hypusinate eIF5a in stromal cells to prevent interferon production and thus promote viral replication 22 . This same mechanism may be induced by spermidine to prevent DC activation however it is also possible that hypusination alters mitochondrial capacity and the OXPHOS pathway which itself leads to an immunosuppressive state.…”

Assessment of The Broad-Spectrum Host Targeting Antiviral Efficacy of Halofuginone Hydrobromide in Human Airway, Intestinal and Brain Organoid Models

“…One of its main functions is to facilitate the translation of PP-motifs (Schuller et al, 2017). Simultaneously, during viral infection, eIF5A is upregulated to promote viral translation (Seoane et al, 2022). The upregulation of eIF5A may counteract the effect of HH, and therefore not completely inhibit viral protein formation.…”