Tnfaip3, commonly referred to as A20, is an integral part of the ubiquitin-editing complex and a critical negative regulator of immune activation [2,4]. It significantly influences immune regulation, apoptosis, and the initiation of diverse immune responses. A20 targets diverse proteins involved in pleiotropic immunologic pathways, especially those related to the NF-κB signaling pathway [1,2,4]. Persistent activation of NF-κB is central to the pathogenesis of many inflammatory disorders, and A20 acts as an endogenous negative regulator of this signaling [1].

In a mouse model with a Tnfaip3 reduction-of-function coding variant (Tnfaip3I325N), female mice exhibited reduced fecundity, associated with irregular estrous cycling, low numbers of ovarian secondary follicles, impaired mammary gland development, and insulin resistance. Transplantation experiments pointed towards a cell-extrinsic hormonal mechanism. Additionally, there was increased microglial activation in the hypothalamus with reduced luteinizing hormone levels, suggesting a link between Tnfaip3 and neuronal inflammatory homeostasis [3].

In conclusion, Tnfaip3 plays a crucial role in immune regulation, apoptosis, and the NF-κB signaling pathway. Mouse models with Tnfaip3 reduction-of-function have revealed its role in female fertility and CNS inflammation, highlighting its significance in these biological processes and disease-related areas.