Integrative genomics approach leads to new insights into antiviral immunity

Lee , Van Der Robin

In a recent publication in PLoS Computational Biology, Robin van der Lee (photo), Martijn Huynen and colleagues (Centre for Molecular and Biomolecular Informatics, CMBI) describe a novel framework that systematically explores a wide variety of genome-scale data to computationally predict novel regulators of a key antiviral pathway in human innate immunity: the RIG-I-like receptor (RLR) pathway. Collaboration with the Virology Division in Utrecht (Qian Feng, Martijn Langereis and Frank van Kuppeveld) led to experimental confirmation of ~100 novel predicted RLR pathway components. The study expands the collection of known antiviral genes, opening up new avenues for research into innate antiviral immunity. The complete resource of predicted and validated RLR pathway components is available at: link

Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response. PLoS Comput Biol 11(10): e1004553

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 , obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research."

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