Zika virus protein NS4B modulates mitochondrial morphodynamics during the infection
Wesley Freppel1,2, Anaïs Anton1,2, Clément Mazeaud1,2 and Laurent Chatel-Chaix1,2*
1Institut national de la recherche scientifique, Centre INRS-Institut Armand-Frappier; Centre de recherche BioMed.
Following serious recent outbreaks in pacific islands and in the Americas, Zika virus (ZIKV) currently constitutes a major public health concern worldwide. Notably, ZIKV infection can cause congenital microcephaly in addition to other neurological complications. Most importantly, neither antivirals nor vaccines are available against this pathogen.
In order to generate an intracellular environment favorable to viral replication, ZIKV remodels cellular endomembranes, including endoplasmic reticulum from which viral replication factories originate. Moreover, we have recently demonstrated that infection of hepatoma cells with either historical or epidemic strains of ZIKV induces a drastic elongation of mitochondria (Chatel-Chaix et al., Cell Host & Microbe, 2016). We now show that the non-enzymatic ZIKV NS4B protein which is absolutely required for RNA replication, is responsible for this elongation phenotype when transiently expressed as a mature or precursor protein. This correlated with a loss of phosphorylation-dependent activation of the mitochondria fission factor Dynamin-Related Protein-1 (DRP1), hence influencing the fission/fusion equilibrium in favor of elongation. Importantly, enforced mitochondria elongation through DRP1 expression knockdown promoted ZIKV replication, highlighting that mitochondria morphodynamics influence ZIKV life cycle. These results are reminiscent of the ones previously obtained for dengue virus, another flavivirus closely related to ZIKV, for which mitochondrial elongation was also shown to alleviate early innate immune responses. Considering this, we propose that these viruses share similar strategies relying on the perturbation of mitochondria morphodynamics to dampen cellular antiviral responses and hence, to promote viral replication.
Since flaviviral NS4B is the target of several antiviral drugs currently in pre-clinical development, the functional interface between ZIKV NS4B and mitochondria might constitute an attractive drug target. Further ongoing experiments aiming at characterizing the impact of this ZIKV-mediated mitochondrial hijacking in the modulation of cellular processes will be presented.