Hidden Heroes: Nuclear RNA-binding proteins and their secret antiviral powers

Alfredo Castello

MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, 464 Bearsden Road, Glasgow G61 1QH, Scotland (UK), Alfredo.Castello@glasgow.ac.uk

RNA-binding proteins (RBPs) are emerging as central regulators of antiviral defence, yet their roles in infection remain largely unknown. In this talk, we unveil a hidden layer of host innate immunity orchestrated by nuclear RBPs, a class of proteins traditionally known for regulating gene expression and RNA metabolism. Using integrative proteomics, systems virology, and functional assays, we discovered that a substantial cohort of nuclear RBPs is relocalised during infection and exerts potent antiviral functions. These proteins can restrict diverse RNA viruses, acting at multiple stages of the viral lifecycle. Amongst these nuclear RBPs, we discovered that the U2 snRNP has roles beyond splicing, moonlighting as an antiviral complex driven by an RNA molecule in analogy to the RNAi pathway. Our work reveals that the nucleus is not just a passive target of viral manipulation, but a proactive hub of host defence. This overlooked antiviral axis opens up new therapeutic avenues and reshapes how we think about innate immunity in the RNA–protein world.

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