Abstract
The rapidly emerging human health crisis associated with the Zika virus (ZIKV) epidemic and its link to severe complications highlights the growing need to identify the mechanisms by which ZIKV accesses hosts. Interferon response protects host cells against viral infection, while the cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, only a few have been characterized for their antiviral potential, target specificity and mechanisms of action. In this work, we focused our investigation on the possible antiviral effect of a novel ISG, C19orf66 in response to ZIKV infection and the associated mechanisms. We found that ZIKV infection could induce C19orf66 expression in ZIKV-permissive cells, and such an overexpression of C19orf66 remarkably suppressed ZIKV replication. Conversely, the depletion of C19orf66 led to a significant increase in viral replication. Furthermore, C19orf66 was found to interact and co-localize with ZIKV nonstructural protein 3 (NS3), thus inducing NS3 degradation via a lysosome-dependent pathway. Taken together, this study identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically degrading a viral nonstructural protein. These findings uncovered an intriguing mechanism of C19orf66 that targeting NS3 protein of ZIKV, providing clues for understanding the actions of innate immunity, and affording the possible availability of new drug targets that can be used for therapeutic intervention.
Highlights
Zika virus (ZIKV) belongs to the family Flaviviridae, which is mainly transmitted by Aedes mosquitoes
This work described our novel finding of the antiviral effect of a novel interferon-stimulated genes (ISGs), C19orf66, and its underlying mechanisms
We identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by interacting and colocalizing with the ZIKV nonstructural (NS) protein nonstructural protein 3 (NS3), which inducing NS3 degradation via a lysosome-dependent pathway
Summary
Zika virus (ZIKV) belongs to the family Flaviviridae (genus Flavivirus), which is mainly transmitted by Aedes mosquitoes. Despite that the major clinical syndromes caused by ZIKV are self-limited acute fever, rash, arthralgia, and conjunctivitis, until now ZIKV represents a serious threat to global health and was declared an international emergency by the World Health Organization, with particular relevance to microcephaly and other congenital abnormalities in newborns, and Guillain-Barresyndrome, meningoencephalitis, and multiorgan failure in adults, which is the most striking and has never been observed in infection with any other flavivirus, like DENV, or yellow fever virus (YFV) [1, 3]. There are no clinically approved vaccines or drugs available for ZIKV infection or its associated diseases, and patients are dependent on innate and adaptive parts of the host immune response to fight the infection [1]. There is a pressing need for a comprehensive understanding of the molecular pathogenesis of ZIKV and the host immune response, to aid in the development of effective vaccines and antiviral therapies
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