Abstract
The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50%) that affected viral RNA-induced production of IFNβ. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1), and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1). Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/), obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research.
Highlights
Viruses are a major cause of human disease, as highlighted by the pandemics of influenza viruses, HIV–1, and the current outbreak of the Ebola virus
We investigated whether available genomics data contain sufficient signal to accurately describe RIG-I-like receptor (RLR) pathway components, and whether such data could be used to prioritize novel genes for a possible role in RLR signaling
To discover molecular signatures that distinguish RLR pathway components from other genes, we explored a wide variety of genome-scale data describing different aspects of the virology and biology of the pathway
Summary
Viruses are a major cause of human disease, as highlighted by the pandemics of influenza viruses, HIV–1, and the current outbreak of the Ebola virus. Activation of the receptors triggers a complex signaling network, key steps of which are the activation of the mitochondrial adapter MAVS, subsequent recruitment of the TBK1 and IKK complexes, phosphorylation/activation of IRF3 and NFκB, and translocation of these transcription factors to the nucleus. These steps lead to the production of type I interferons (IFNα/β) and proinflammatory cytokines, which are crucial for establishing an antiviral state in infected as well as neighboring cells, and modulate the adaptive immune response [4]
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