Abstract
Peroxisomes are recognized as significant platforms for the activation of antiviral innate immunity where stimulation of the key adapter molecule mitochondrial antiviral signaling protein (MAVS) within the RIG-I like receptor (RLR) pathway culminates in the up-regulation of hundreds of ISGs, some of which drive augmentation of multiple innate sensing pathways. However, whether ISGs can augment peroxisome-driven RLR signaling is currently unknown. Using a proteomics-based screening approach, we identified Pex19 as a binding partner of the ISG viperin. Viperin colocalized with numerous peroxisomal proteins and its interaction with Pex19 was in close association with lipid droplets, another emerging innate signaling platform. Augmentation of the RLR pathway by viperin was lost when Pex19 expression was reduced. Expression of organelle-specific MAVS demonstrated that viperin requires both mitochondria and peroxisome MAVS for optimal induction of IFN-β. These results suggest that viperin is required to enhance the antiviral cellular response with a possible role to position the peroxisome at the mitochondrial/MAM MAVS signaling synapse, furthering our understanding of the importance of multiple organelles driving the innate immune response against viral infection.
Highlights
The innate immune response to viral infection is crucial in virus control and dissemination and is initiated by cellular recognition of viral genetic and nongenetic components expressed during viral replication
After stringent analysis to remove false positives, we identified 10 cDNA fragments that were subsequently confirmed in a second-round Y2H assay that identified peroxisomal biogenesis factor 19 (Pex19) as a genuine interacting partner with viperin
Pex19 is a cytoplasmic chaperone protein that in combination with Pex3 is responsible for the transport of peroxisomal membrane proteins (PMPs) to this organelle and is important for peroxisome integrity (Sacksteder et al, 2000; Jones et al, 2004)
Summary
The innate immune response to viral infection is crucial in virus control and dissemination and is initiated by cellular recognition of viral genetic and nongenetic components expressed during viral replication. In the case of RNA virus infection, the best-characterized Pattern Recognition Receptors are the membrane-bound TLRs and the cytoplasmic RNA-sensing helicases, RIG-I and MDA5 (Jensen & Thomsen, 2012) After binding of these helicases with viral RNA, they interact with the adaptor protein mitochondrial antiviral signaling protein (MAVS), which is localized to a diverse set of membranes including the mitochondria, mitochondrial associated membranes (MAM, a subdomain of the ER), and peroxisomes that drive production of the type-I and type-III IFNs (Horner et al, 2011). In some instances, ISG expression can be induced independently of IFN stimulation (Collins et al, 2004) These ISGs inhibit viral replication and drive the inflammatory process to generate an antiviral state (Schoggins, 2019). The importance of this system is exemplified by the fact that most viruses have evolved mechanisms to evade or inactivate the IFN response by suppression of innate immune signaling cascades (Beachboard & Horner, 2016)
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