Transglutaminase 2 regulates innate immunity: mechanisms and therapeutic implications

Innate immunity constitutes the primary barrier against invading pathogens and plays a crucial role in coordinating the initiation and modulation of adaptive immune responses. Transglutaminase 2 (TG2), a ubiquitously expressed multifunctional enzyme, has recently been identified as a key regulator of innate immune signaling. Mounting evidence highlights TG2's involvement in modulating type I interferons and pro-inflammatory cytokines in response to microbial infections and cellular stress, serving as an critical element in diverse signaling pathways. TG2 engages in various immune-related processes, such as inflammation, phagocytosis, and host defense, by integrating into essential intracellular signaling cascades. In this review, we synthesize the current knowledge of TG2's roles in the innate immune system, emphasizing its interactions with TBK1 (TANK-binding kinase 1)-a central node in type I interferon signaling-and other innate immune mediators. We also examine the implications of TG2 dysregulation in immune-mediated diseases and evaluate its promise as a therapeutic target. Collectively, this review integrates recent progress and encourages further exploration of TG2's multifaceted contributions to innate immunity.