Role of peroxisomes and PEX19 in Zika and Dengue virus host-pathogen interactions
Creators: name: DE ARRÁBIDA FARELO, MAFALDA
Publisher: name: University of Surrey
Year: 2020

description: Peroxisomes are mostly known for their role in metabolism, however the focus on this organelle has recently shifted to other roles. Peroxisomes have emerged as platforms for antiviral innate immunity since the discovery that MAVS, a tail-anchored protein that mediates the induction of antiviral innate immunity pathways, is present in the membranes of peroxisomes. Subsequently, some viruses were found to escape the peroxisome-mediated antiviral response, either directly, by inhibiting peroxisomal MAVS, or indirectly, by affecting peroxisome homeostasis.
description: Viruses within the Flavivirus genus were described to cause peroxisome depletion and inhibition of antiviral immunity. Interestingly, interaction between the viral capsid protein (C) and PEX19, an important chaperone in peroxisome biogenesis, was reported and suggested to be the mechanism behind viral-induced peroxisome depletion. Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses found in tropical and sub-tropical regions. Infection by DENV or ZIKV may develop into severe viral-associated pathologies, such as vascular leakage in DENV or neurologic disorders in ZIKV. Despite their clinical relevance, effective antiviral treatments and vaccines are yet to be developed. Therefore, it is important to understand the host-pathogen interaction of these viruses in order to find new targets for future therapies. Here we investigate the role of peroxisomes and PEX19 in the host-pathogen interaction of two flaviviruses, DENV and ZIKV, and the importance of peroxisomes in their viral life cycle. Moreover, we explore the mechanisms of MAVS sorting and transport to peroxisomes.
description: Interaction between DENV C and PEX19 was confirmed and a novel interaction between ZIKV C and PEX19 was found by pull-down assays and Co-IPs. We show that both ZIKV and DENV C proteins have a conserved PEX19 binding domain, which is shared with other peroxisomal membrane proteins (PMPs), and can be disrupted by exchange of key amino acids. However, unlike PMPs, C proteins do not localize to peroxisomes. We also show that presence of ZIKV C protein results in peroxisome loss, which appears to occur by a PEX19-independent mechanism. Furthermore, we demonstrate that peroxisome loss occurs by impairment of peroxisomal biogenesis. DENV infection of control or peroxisome-less fibroblasts shows that peroxisomes have an important role in the viral life cycle, as absence of peroxisomes results in reduced DENV titers.
description: Regarding MAVS sorting to organelles, we demonstrate that the C-terminus of MAVS dictates the protein’s subcellular localization, and therefore we used miniMAVS (which lacks MAVS N-terminus) in our studies. We show that miniMAVS localizes to peroxisomes and binds to PEX19, which suggests it is transported to peroxisomes by this chaperone. Furthermore, the charge of miniMAVS tail influences the localization to peroxisomes, as tails containing more positive charges result in higher localization to peroxisomes and more negatively charged tails result in reduced peroxisomal localization. Preliminary studies suggest that presence of ZIKV C does not appear to alter MAVS localization to peroxisomes.
description: This study challenges the current model, suggesting that peroxisome depletion by Flavivirus infection is PEX19-independent, and gathers evidence that highlights the importance of peroxisomes in the Flavivirus life cycle. Peroxisomes have essential roles in neurologic development and function, these organelles should be considered in the study of pathobiology of ZIKV infection in the CNS.