EFhd2, also known as Swiprosin-1, is a Ca2+ sensor protein with immunomodulatory effects. It has been implicated in multiple biological pathways such as calcium signaling, apoptosis, and actin cytoskeleton regulation. EFhd2 is highly expressed in the brain and immune cells, suggesting its importance in neuronal circuits, behavior, and the immune system [3,4,5]. Genetic models like knockout (KO) mice are valuable for studying its functions.

In non-alcoholic steatohepatitis (NASH), EFhd2 deletion, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited ferroptosis, and attenuated fibrosis. Myeloid EFhd2 deletion also prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed decreases in patrolling monocytes and CD4+/CD8+ T cell ratio. Mechanistically, EFhd2 in myeloid cells interacts with YWHAZ, facilitating IFNγR2 translocation and mediating interferon-γ signaling [1]. In intestinal epithelial cells, Efhd2 deficiency led to excessive cell death and exacerbated experimental colitis as EFhd2 inhibits TNF-induced apoptosis by blocking TNFR1 internalization [2]. In sepsis, Efhd2-deficient CD4+ T cells showed impaired T cell receptor-induced Th1 and Th17 differentiation, along with reduced levels of related phosphorylated proteins and transcription factors [6].

In conclusion, EFhd2 plays crucial roles in multiple biological processes and disease conditions. Model-based research, especially KO mouse models, has revealed its importance in NASH, intestinal inflammation, and sepsis. Understanding EFhd2's functions provides potential therapeutic targets for these diseases.

References:

1. Fu, Jiang-Tao, Liu, Jian, Wu, Wen-Bin, Wang, Zhi-Bin, Wang, Pei. 2024. Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis. In Journal of hepatology, 81, 389-403. doi:10.1016/j.jhep.2024.04.009. https://pubmed.ncbi.nlm.nih.gov/38670321/

2. Wu, Jiacheng, Xu, Xiaoqing, Duan, Jiaqi, Li, Jingnan, Cao, Xuetao. 2024. EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death. In Nature communications, 15, 1282. doi:10.1038/s41467-024-45539-x. https://pubmed.ncbi.nlm.nih.gov/38346956/

3. Kogias, Georgios, Kornhuber, Johannes, Reimer, Dorothea, Mielenz, Dirk, Müller, Christian P. . Swiprosin-1/ EFhd2: from Immune Regulator to Personality and Brain Disorders. In Neuro-Signals, 27, 1-19. doi:10.33594/000000179. https://pubmed.ncbi.nlm.nih.gov/31742960/

4. Thylur Puttalingaiah, Ramesh. 2022. Role of Swiprosin-1/EFHD2 as a biomarker in the development of chronic diseases. In Life sciences, 297, 120462. doi:10.1016/j.lfs.2022.120462. https://pubmed.ncbi.nlm.nih.gov/35276221/

5. Vega, Irving E. 2016. EFhd2, a Protein Linked to Alzheimer's Disease and Other Neurological Disorders. In Frontiers in neuroscience, 10, 150. doi:10.3389/fnins.2016.00150. https://pubmed.ncbi.nlm.nih.gov/27064956/

6. Zhang, Wenzhao, Chen, Linlin, Lu, Xin, Tu, Ye, Wang, Zhibin. 2024. EFHD2 regulates T cell receptor signaling and modulates T helper cell activation in early sepsis. In International immunopharmacology, 133, 112087. doi:10.1016/j.intimp.2024.112087. https://pubmed.ncbi.nlm.nih.gov/38669951/