RIG-I, short for retinoic acid-inducible gene I, is a key cytoplasmic RNA helicase and pattern recognition receptor in the innate immune system [1,3,4,5,6]. It detects viral RNA as a pathogen-associated molecular pattern (PAMP), triggering type I interferon (IFN)-mediated antiviral immune responses through the MAVS-IRF-3 axis [3,6]. RIG-I signaling also plays a role in other processes like DNA repair and cancer immunotherapy [4,7]. Genetic models, especially knockout (KO) mouse models, are crucial for studying RIG-I's functions.

In IFI16 knockout cells and p204-deficient mice, the DNA sensor IFI16 was found to enhance RIG-I transcription and activation, inhibiting influenza A virus replication [1]. In CD8+ T cells, intrinsic Rig-I deficiency or inhibition enhanced the tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells, indicating that RIG-I restrains the antitumor activity of CD8+ T cells by restraining STAT5 activation [4]. In addition, a novel DDX58 pathogenic variant (R109C) causing lupus nephritis was identified, with the variant leading to RIG-I hyperactivation, increased RIG-I K63 ubiquitination, and MAVS aggregation [2].

In conclusion, RIG-I is essential for innate antiviral immunity, and its dysregulation can be involved in diseases such as influenza virus infection, lupus nephritis, and cancer. Studies using KO mouse models have provided valuable insights into RIG-I's functions in these disease conditions, helping to understand the underlying mechanisms and potentially guiding the development of targeted therapies.