The alternative cap-binding complex is required for antiviral defense in vivo.

Cellular response to environmental challenges requires immediate and precise regulation of transcriptional programs. During viral infections, this includes the expression of antiviral genes that are essential to combat the pathogen. Transcribed mRNAs are bound and escorted to the cytoplasm by the cap-binding complex (CBC). We recently identified a protein complex consisting of NCBP1 and NCBP3 that, under physiological conditions, has redundant function to the canonical CBC, consisting of NCBP1 and NCBP2. Here, we provide evidence that NCBP3 is essential to mount a precise and appropriate antiviral response. Ncbp3-deficient cells allow higher virus growth and elicit a reduced antiviral response, a defect happening on post-transcriptional level. Ncbp3-deficient mice suffered from severe lung pathology and increased morbidity after influenza A virus challenge. While NCBP3 appeared to be particularly important during viral infections, it may be more broadly involved to ensure proper protein expression. Author summary Infection with viruses and other pathogens requires appropriate cellular countermeasures, which involve swift and accurate adaptation of gene expression profiles. mRNAs encoding for immune-regulatory and effector proteins need to be transported into the cytoplasm in order to generate proteins necessary to fight the pathogen. Here we show that this process requires proper functionality of the Nuclear cap protein 3 (NCBP3), a protein recently identified to contribute to an alternative mRNA cap-binding complex. An Ncbp3-deficient mouse model allowed higher virus growth in vitro and showed high susceptibility to influenza A virus challenge in vivo. While NCBP3-deficient cells were able to transcriptionally upregulate cytokine mRNAs, generation of cytokines was significantly reduced in the absence of NCBP3. Our data shows a non-redundant function of NCBP3 and the alternative cap-binding complex in antiviral responses. More broadly, this work demonstrates a yet unappreciated aspect of post-transcriptional gene regulation.