hnRNPA1 impedes snakehead vesiculovirus replication via competitively disrupting viral phosphoprotein-nucleoprotein interaction and degrading viral phosphoprotein

Abstract

Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) plays an important role in regulating the replication of many viruses. However, it remains elusive whether and how hnRNPA1 regulates fish virus replication. In this study, the effects of twelve hnRNPs on the replication of snakehead vesiculovirus (SHVV) were screened. Three hnRNPs, one of which was hnRNPA1, were identified as anti-SHVV factors. Further verification showed that knockdown of hnRNPA1 promoted, while overexpression of hnRNPA1 inhibited, SHVV replication. SHVV infection reduced the expression level of hnRNPA1 and induced the nucleocytoplasmic shuttling of hnRNPA1. Besides, we found that hnRNPA1 interacted with the viral phosphoprotein (P) via its glycine-rich domain, but not with the viral nucleoprotein (N) or large protein (L). The hnRNPA1-P interaction competitively disrupted the viral P-N interaction. Moreover, we found that overexpression of hnRNPA1 enhanced the polyubiquitination of the P protein and degraded it through proteasomal and lysosomal pathways. This study will help understanding the function of hnRNPA1 in the replication of single-stranded negative-sense RNA viruses and providing a novel antiviral target against fish rhabdoviruses.

hnRNPs: roles in neurodevelopment and implication for brain disorders

“…As an example, during HIV-1 infection, hnRNP A1 expression is increased ( Monette et al, 2009 ) while hnRNPs A2/B1 and H are decreased ( Dowling et al, 2008 ). Conversely, expression of a given hnRNP could be either increase or decrease depending on the nature of the virus as shown for hnRNP A1 that is upregulated during influenza A virus (IAV), HIV-1 ( Monette et al, 2009 ), and HPV16 ( Cheunim et al, 2008 ) infections, and downregulated during infections with porcine epidemic diarrhea virus or snakehead vesiculovirus ( Li et al, 2018 ; Kaur et al, 2022 ; Liu et al, 2023 ). Moreover many hnRNPs [hnRNP D ( Lund et al, 2012 ), hnRNP A1, hnRNP K, hnRNP C1/C2 ( Pettit Kneller et al, 2009 ), hnRNP K ( Burnham et al, 2007 ; Brunetti et al, 2015 ), hnRNP H ( Redondo et al, 2015 ), and hnRNP M ( Jagdeo et al, 2015 )] have been shown to relocalize to the cytoplasm following infection with various viruses.…”