c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis.

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.

ZIKV induces P62-mediated autophagic degradation of TRAF6 through TRAF6-NS1 interaction.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.