C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3

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. "Guangdong Te Zhi program" youth science and technology talent of project (2015TQ01R281); Guangdong MEDP Fund Author summary ZIKV represents a serious threat to global health with particular relevance to microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. Despite the global health threat of Zika virus infection, there is currently no vaccine or effective antiviral therapy available for the disease. As widely recognized, interferon signaling is key to establishing a strong antiviral state in host cells, mainly mediated through the anti-viral effects of numerous interferon-stimulated genes (ISGs). This work described our novel finding of the antiviral effect of a novel ISG, C19orf66, and its underlying mechanisms. We identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically interacting and colocalizing with the ZIKV nonstructural (NS) protein NS3, which inducing NS3 degradation via a lysosome-dependent pathway. Thus, this work broadens the understanding of the pivotal roles of C19orf66 in the interaction between the host and ZIKV, which might further provide a rational basis for developing novel anti-ZIKV strategies. PLOS NEGLECTED TROPICAL DISEASESC19orf66 suppresses ZIKV replication by target viral NS3 PLOS Neglected Tropical Diseases | https://doi.org/10.

All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes

“…In uninfected cells, SHFL resides primarily in the cytoplasm in punctate structures, associating with both stress granule and P body proteins in HEK293 and Huh7.5 cells ( 165 , 166 ), but was also more recently identified as an antiviral effector counteracting replication of RNA viruses ( 27 , 28 , 164 , 167 ). For example, SHFL broadly inhibits replication of members of the (+) ssRNA virus family Flaviviridae , including all four DENV serotypes, WNV, ZIKV, and HCV ( 164 – 166 , 168 ). SHFL also inhibits the virion production of chikungunya virus and SINV, members of the (+) ssRNA virus family Togaviridae .…”

“…However, SHFL may also act on some viruses independent of its direct effects on viral translation. For example, SHFL associates with the flavivirus replication complex in both DENV and ZIKV infections and interacts specifically with nonstructural protein 3 (NS3) in an RNA-independent manner ( 165 , 168 ). By doing so, SHFL induces lysosomal-mediated degradation of NS3 in ZIKV-infected cells.…”

Membrane-Associated Flavivirus Replication Complex—Its Organization and Regulation

“…In recent studies by us and others, C19orf66 was reported as a novel ISG that inhibits DENV, WNV, and ZIKV replication [118][119][120][121]. The ISG initially named RyDEN (Repressor of yield of DENV [118], also referred to as IRAV [119] and Shiftless [122] in subsequent studies) has been identified as a cellular gene exhibiting anti-hepatitis C virus (HCV) activity by Schoggins et al, using an overexpression screening of an ISG library [94].…”

Interferon revisited: Peering behind the lines of antiviral defense

“… 6 Indeed, it was previously described as a potent restriction factor for HIV, Kaposi's sarcoma-associated herpesvirus (KSHV), Zika virus and dengue virus (DENV). [7] , [8] , [9] , [10] However, the molecular details related to the function of C19orf66, especially for HCV, remained largely unknown.…”

“…While many putative functions of C19orf66 may not be relevant to HCV infection, this protein certainly inhibits other viruses with different aspects of its pluripotent nature ( Fig. 1 ), i.e ., triggering the lysosomal degradation of ZIKA NS3, 8 repressing KSHV gene expression, 9 altering crucial Gag/Pol ratios during HIV replication, 10 stress granule formation during DENV 7 and HCV infection, and most likely additional not yet discovered facets of its action relevant to other pathogens. Interestingly, C19orf66 is also induced in the antiviral response to SARS-CoV, 9 where it escapes the virus-induced mRNA degradation, as has been demonstrated for KSHV.…”