Abstract
The tumor suppressor p53 as an innate antiviral regulator contributes to restricting Japanese encephalitis virus (JEV) replication, but the mechanism is still unclear. The interferon-induced transmembrane protein 3 (IFITM3) is an intrinsic barrier to a range of virus infection, whether IFITM3 is responsible for the p53-mediated anti-JEV response remains elusive. Here, we found that IFITM3 significantly inhibited JEV replication in a protein-palmitoylation-dependent manner and incorporated into JEV virions to diminish the infectivity of progeny viruses. Palmitoylation was also indispensible for keeping IFITM3 from lysosomal degradation to maintain its protein stability. p53 up-regulated IFITM3 expression at the protein level via enhancing IFITM3 palmitoylation. Screening of palmitoyltransferases revealed that zinc finger DHHC domain-containing protein 1 (ZDHHC1) was transcriptionally up-regulated by p53, and consequently ZDHHC1 interacted with IFITM3 to promote its palmitoylation and stability. Knockdown of IFITM3 significantly impaired the inhibitory role of ZDHHC1 on JEV replication. Meanwhile, knockdown of either ZDHHC1 or IFITM3 expression also compromised the p53-mediated anti-JEV effect. Interestingly, JEV reduced p53 expression to impair ZDHHC1 mediated IFITM3 palmitoylation for viral evasion. Our data suggest the existence of a previously unrecognized p53-ZDHHC1-IFITM3 regulatory pathway with an essential role in restricting JEV infection and provide a novel insight into JEV-host interaction.
Highlights
Japanese encephalitis virus (JEV) is a zoonotic mosquito-borne virus belonging to the genus Flavivirus in the family Flaviviridae that comprises more than 70 species including Dengue virus (DENV), West Nile virus (WNV) and Zika virus (ZIKV)
We explored the downstream molecules responsible for the p53-mediated anti-JEV response. p53 transcriptionally up-regulated the expression of the palmitoyltransferase zinc finger DHHC domain-containing protein 1 (ZDHHC1) to enhance stability of the antiviral restriction factor interferon-induced transmembrane protein 3 (IFITM3) by regulating its palmitoylation
Exogenous expression of interferoninduced transmembrane protein 3 (IFITM3) following transfecting with HA-tagged IFITM3 plasmid (HA-IFITM3) significantly reduced the JEV titre and NS3 protein level compared with vector-transfected cells (Fig 1C and 1D)
Summary
Japanese encephalitis virus (JEV) is a zoonotic mosquito-borne virus belonging to the genus Flavivirus in the family Flaviviridae that comprises more than 70 species including Dengue virus (DENV), West Nile virus (WNV) and Zika virus (ZIKV). It is responsible for encephalitis in humans and reproductive disorders in pigs, with important impacts on both human public health and the pig industry [1]. Tumor suppressor p53, a well-known transcription factor for guarding the genome stability, contributes to the host antiviral response against a number of viruses infection through modulating innate immune response, host cell cycling and apoptosis [2,3,4]. We previously demonstrated that p53 functioned as an essential antiviral molecule against JEV replication in vitro and in vivo [11]; the mechanism responsible for the p53-mediated anti-JEV response remains unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
