Innate immune responses are crucial for defense against infectious agents, but the inherent danger of pathological inflammation and tissue damage highlights the need for rigorous control mechanisms. van Bakel, Marazzi and colleagues now uncover an unanticipated role for the helicase senataxin (SETX) in inhibiting the cellular transcriptional response to viral infection. The authors show that SETX specifically promotes premature promoter-proximal termination at genes whose expression is dependent on the interferon regulatory transcription factor IRF3. Interestingly, Sen1, the yeast ortholog of SETX, was known to track along nascent RNA and induce early termination at noncoding-RNA loci. Accordingly, SETX is able to bind RNA derived from the 5′ ends of antiviral genes, and expression of wild-type SETX, but not mutants lacking either ATPase or RNA-binding activity, increases the amount of short RNAs associated with transcription start sites. SETX-mediated termination might thus depend on sequence-specific recognition of target RNAs or be driven by interaction with structural elements formed at nascent transcripts. In addition, SETX interacts with the transcription-initiation factor TAF4, previously proposed to coordinate transcriptional responses by acting as a binding platform for both positive and negative regulators. Importantly, congenital SETX mutations have been linked to neurodegenerative diseases, and the authors now show that patient-derived cell lines display an augmented antiviral response, an observation that can be recapitulated in a Setx-knockout mouse model. These results lend support to the idea that excessive inflammation might contribute to neurological disorders. (Nat. Immunol. doi:10.1038/ni.3132, published online 30 March 2015).