Abstract
The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named “NS-degradasome” (NSD). The NSD is roughly ∼300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity.
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Acknowledgements
This research was supported in part by an Ohio Third Frontier Grant, cost-share funds from the Provost and the Research office of the Cleveland State University (CSU), NIH 1 S10 OD010381 (all to SB) and NIH grants (AI073303 and CA068782 to GCS). We are indebted to Chris Basler, Adolfo García-Sastre (Mount Sinai School of Medicine, NY, USA), Carl Ware (Sanford Burnham Medical Research Institute, La Jolla, USA) and Michael Gale (University of Washington, Seattle, USA) for various recombinant plasmids of the IFN pathway genes, and to Michael Gale for the NS3/4A-expressing cell line.
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Goswami, R., Majumdar, T., Dhar, J. et al. Viral degradasome hijacks mitochondria to suppress innate immunity. Cell Res 23, 1025–1042 (2013). https://doi.org/10.1038/cr.2013.98
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DOI: https://doi.org/10.1038/cr.2013.98
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