Tnfaip3, also known as A20, is a crucial negative regulator of immune activation. It is a ubiquitin-editing enzyme with multiple domains, mediating or stabilizing key ubiquitin modifications. A20 targets various proteins in pleiotropic immunologic pathways, and its deletion has diverse effects in different cell types and disease models. It is involved in pathways like NF-κB signaling, which is central to many inflammatory and immune-related processes [1,3].

In a mouse model with a Tnfaip3 reduction-of-function coding variant (Tnfaip3I325N), reduced fecundity was observed. This was associated with irregular estrous cycling, low ovarian secondary follicle numbers, impaired mammary gland development, and insulin resistance. Transplantation experiments pointed towards a cell-extrinsic hormonal mechanism. Also, increased microglial activation and reduced luteinizing hormone levels were seen in hypothalamic brain sections, highlighting a link between Tnfaip3 and neuronal inflammatory homeostasis [2].

In conclusion, Tnfaip3 is essential in immune regulation and ubiquitination processes. The Tnfaip3 reduction-of-function mouse model reveals its role in female fertility and CNS inflammation. Understanding Tnfaip3's functions through such models can provide insights into the pathogenesis of related diseases, potentially guiding future therapeutic strategies.

References:

1. Bagyinszky, Eva, An, Seong Soo A. 2024. Genetic Mutations Associated With TNFAIP3 (A20) Haploinsufficiency and Their Impact on Inflammatory Diseases. In International journal of molecular sciences, 25, . doi:10.3390/ijms25158275. https://pubmed.ncbi.nlm.nih.gov/39125844/

2. Zammit, Nathan W, McDowell, Joseph, Warren, Joanna, Oakes, Samantha R, Grey, Shane T. 2022. TNFAIP3 Reduction-of-Function Drives Female Infertility and CNS Inflammation. In Frontiers in immunology, 13, 811525. doi:10.3389/fimmu.2022.811525. https://pubmed.ncbi.nlm.nih.gov/35464428/

3. Karri, Urekha, Harasimowicz, Magdalena, Carpio Tumba, Manuel, Schwartz, Daniella M. 2024. The Complexity of Being A20: From Biological Functions to Genetic Associations. In Journal of clinical immunology, 44, 76. doi:10.1007/s10875-024-01681-1. https://pubmed.ncbi.nlm.nih.gov/38451381/