DDX58

DDX58, also known as RIG-I (retinoic acid-inducible gene I), is a cytosolic pattern recognition receptor that detects viral RNA and initiates innate immune signaling. It is a member of the RIG-I-like receptor (RLR) family, which also includes MDA5 and LGP2. Expression of DDX58 can be induced by interferons and during viral infection, aligning its activity with cellular antiviral states.

The DDX58 gene encodes a protein organized into a N-terminal pair of caspase activation and recruitment domains (CARDs), a central DEAD-box helicase/ATPase domain, and a C-terminal regulatory RNA-binding domain. In resting cells, RIG-I is auto-inhibited; binding to viral RNA—particularly 5'-triphosphate-containing RNA or short double-stranded RNA—induces conformational changes that expose the CARDs. The CARDs are further activated by K63-linked ubiquitination, primarily mediated by the E3 ligase TRIM25 (with involvement of RIPLET in some contexts). Activated RIG-I then interacts with the mitochondrial adaptor MAVS, triggering a signaling cascade through TBK1/IKKε and IKK, leading to the activation of transcription factors IRF3/IRF7 and NF-κB and resulting in the production of type I interferons and other cytokines.

RIG-I recognizes a broad range of RNA viruses, including influenza A, West Nile virus, and hepatitis C virus, among others. Its signaling is tightly regulated by post-translational modifications and viral antagonists; for example, influenza NS1 can inhibit RIG-I signaling. Dysregulation of DDX58 signaling has been linked to altered antiviral responses and has been investigated in the context of autoinflammatory and inflammatory conditions, as well as in antiviral therapeutic strategies.