Ciao2a, also known as Fam96A, is an evolutionarily conserved protein. It is a cytosolic Fe-S assembly protein involved in regulating cellular Fe homeostasis [2]. It may also be associated with pathways such as interferon/STAT1 signaling, mTOR signaling, and TGFβ1 signaling, and is important for maintaining organismal energy balance, adipose tissue homeostasis, and host control of Toxoplasma gondii infection [1,2,3]. Gene knockout mouse models have been crucial in studying its functions.

In myeloid cell-specific Fam96a knockout mice, acute and chronic toxoplasmosis was exacerbated. This was due to defective macrophage polarization, inhibited induction of immune effector molecules like iNOS, and disrupted iron homeostasis [1]. Global Fam96a knockout in mice led to adipocyte hypertrophy, reduced organismal energy expenditure, and mitochondrial defects in brown adipocytes [2]. Adipocyte-selective knockout also showed adipocyte hypertrophy and energy expenditure defects but with resistance to high-fat diet-induced weight gain [2]. In tumor-related studies, FAM96A-knockout tumor cells had enhanced colonization and metastatic abilities in vivo, as FAM96A inhibits TGFβ-mediated tumor metastasis and EMT [3]. In sepsis models, Fam96a-/-mice resisted lesions better, with promoted M2 macrophage transformation and a shift from oxidative phosphorylation to glycolysis in macrophages [4]. In a colitis model, Fam96a-/-mice had increased susceptibility to DSS-induced colitis due to gut microbial dysbiosis [5].

In conclusion, Ciao2a plays essential roles in multiple biological processes including host-pathogen interactions, energy metabolism, and tumor metastasis. The use of KO/CKO mouse models has revealed its significance in diseases such as toxoplasmosis, obesity-related disorders, tumor metastasis, sepsis, and colitis. These studies provide insights into the underlying mechanisms and potential therapeutic targets related to these diseases.

References:

1. Liu, Zhuanzhuan, Wang, Hanying, Zhang, Zhiwei, Wang, Lu, Wang, Yugang. 2024. Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism. In PLoS neglected tropical diseases, 18, e0012163. doi:10.1371/journal.pntd.0012163. https://pubmed.ncbi.nlm.nih.gov/38713713/

2. Liu, Zhuanzhuan, Xu, Shihong, Zhang, Zhiwei, Wang, Lu, Wang, Yugang. 2022. FAM96A is essential for maintaining organismal energy balance and adipose tissue homeostasis in mice. In Free radical biology & medicine, 192, 115-129. doi:10.1016/j.freeradbiomed.2022.09.011. https://pubmed.ncbi.nlm.nih.gov/36150559/

3. Zhao, Ning, He, Minwei, Chen, Wei, Cheng, Xu, Wang, Lu. 2022. FAM96A suppresses epithelial-mesenchymal transition and tumor metastasis by inhibiting TGFβ1 signals. In Life sciences, 301, 120607. doi:10.1016/j.lfs.2022.120607. https://pubmed.ncbi.nlm.nih.gov/35513087/

4. Yin, A, Chen, W, Cao, L, Zhu, X, Wang, L. 2020. FAM96A knock-out promotes alternative macrophage polarization and protects mice against sepsis. In Clinical and experimental immunology, 203, 433-447. doi:10.1111/cei.13555. https://pubmed.ncbi.nlm.nih.gov/33232517/

5. Yin, Ang, Luo, Yang, Chen, Wei, Cao, Lulu, Wang, Lu. 2019. FAM96A Protects Mice From Dextran Sulfate Sodium (DSS)-Induced Colitis by Preventing Microbial Dysbiosis. In Frontiers in cellular and infection microbiology, 9, 381. doi:10.3389/fcimb.2019.00381. https://pubmed.ncbi.nlm.nih.gov/31803631/