When a cell is invaded by a virus, the cell triggers an innate immune response by activating retinoic acid-inducible gene I (RIG-I) like receptors (RLRs), among others, that are essential for controlling viral replication. Even though several ubiquitin ligases (E3) have been identified to positively or negatively regulate RLRs post-translationally, the E3 ligases directly involved in RLR transcription are still unknown. A screening including 375 ubiquitin E3 ligases identified E3 ubiquitin-protein ligase UBR5 as a positive regulator of RLR transcription.