Abstract
The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids. Here we use an affinity proteomics approach in evolutionary distant species (human, mouse and fly) to identify proteins that are conserved in their ability to associate with diverse viral nucleic acids. This approach shows a core of orthologous proteins targeting viral genetic material and species-specific interactions. Functional characterization of the influence of 181 candidates on replication of 6 distinct viruses in human cells and flies identifies 128 nucleic acid binding proteins with an impact on virus growth. We identify the family of TAO kinases (TAOK1, −2 and −3) as dsRNA-interacting antiviral proteins and show their requirement for type-I interferon induction. Depletion of TAO kinases in mammals or flies leads to an impaired response to virus infection characterized by a reduced induction of interferon stimulated genes in mammals and impaired expression of srg1 and diedel in flies. Overall, our study shows a larger set of proteins able to mediate the interaction between viral genetic material and host factors than anticipated so far, attesting to the ancestral roots of innate immunity and to the lineage-specific pressures exerted by viruses.
Highlights
The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids
When using interferon-inducing poly(I:C) for stimulation experiments, we found a significant requirement of TAOK2 to express IFIT1-driven GFP, indicating that the antiviral interferon system was affected by the loss of TAOK2 (Fig. 6e)
The eukaryotic innate immune system coevolved under the selective pressure of viruses over millions of years, which resulted in conserved eukaryotic proteins dedicated to antiviral immunity[8,77]
Summary
The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids. It is commonly accepted that the main pathogen-associated molecular pattern that leads to activation of the innate immune system is viral genetic material, namely viral RNA and DNA3. These nucleic acids (NAs) are delivered into cells upon virus infection and are amplified during viral replication. Specific pattern recognition receptors (PRRs), such as membrane-bound Toll-like receptors (TLRs), cytoplasmic RIG-I-like receptors (RLRs), cGAS, or AIM2-like receptors sense viral nucleic acids and lead to the expression of type-I and type-III (IFN-λ) interferons, which serve as messengers to induce expression of antiviral proteins[4].
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