PTBP1 is upregulated by Zika virus infection via HIF-1alpha signal and hijacks NS1 protein to induce NS1 degradation to restrain viral replication

Abstract

Zika virus (ZIKV), belonging to the Flaviviridae family, has been a severe threat to human health since the worldwide outbreak. ZIKV is capable of inducing fetal microcephaly, Guillain-Barre syndrome, and other serious neurological complications. Polypyrimidine tract-binding protein 1 (PTBP1) is a key member of the heterogeneous nuclear ribonucleoproteins (hnRNPs) family, functioning in selective mRNA splicing and gene expression regulation. Our previous study has indicated that the expression of PTBP1 increases in astrocytes upon ZIKV infection, yet the precise regulatory mechanisms underlying its role in viral replication remain elusive. In this study, we elucidated the specific pathway by which ZIKV upregulates PTBP1 expression through the activation of Hypoxia-inducible factor-1 (HIF-1) expression. Further investigation revealed that overexpression of PTBP1 effectively inhibits viral replication, whereas knockdown of PTBP1 significantly enhances viral replication. Mechanistically, using co-immunoprecipitation assays for protein interaction screening, we identified an interaction between PTBP1 and ZIKV non-structural protein NS1. Detailed studies demonstrated that PTBP1 bound and colocalized with NS1 to lead to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings unveil a novel mechanism underlying that ZIKV infection induces the expression of PTBP1 via the HIF-1 pathway, subsequently the accumulated PTBP1 binds to ZIKV NS1 protein to promote NS1 degradation, thereby effectively inhibiting viral replication. The study illustrates a distinct restricted cellular factor that regulates ZIKV replication, which provides a potential target for the control of the viral replication and pathogenesis during the ZIKV epidemic. ImportanceSince the outbreak of ZIKV infection among human in 2014, a Zika epidemic has caused Zika fever accompanied with fetal microcephaly, Guillain-Barre syndrome, and other neurological symptoms. Emerging evidence reveals that ZIKV infects astrocytes to specially induce the expression of polypyrimidine tract-binding protein 1 (PTBP1), one of hnRNPs members. However, the interplay between PTBP1 and ZIKV replication is highly concerned. Here, we uncover a distinct manner that ZIKV infection induces PTBP1 expression through the activation of hypoxia-inducible factor-1 (HIF-1) signal. Additionally, activation of HIF-1 signal hinders ZIKV replication relying on PTBP1 accumulation. Further investigations suggest that PTBP1 restrains ZIKV replication by interacting with ZIKV NS1 protein, thereby leading to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings illustrate a novel restricted cellular factor PTBP1 mediated by HIF-1 that regulates ZIKV replication, which provides a potential therapeutic target of the viral replication and pathogenesis against ZIKV pandemic.