Emc3, also known as TMEM111, is a subunit of the endoplasmic reticulum membrane complex (EMC). The EMC is involved in the synthesis, trafficking, and quality control of multi-transmembrane-domain proteins, which is crucial for various biological processes such as cell cycle regulation, maintaining organ homeostasis, and tissue development [2,3,4,5]. It participates in pathways like the vesicle trafficking pathway, mitotic spindle assembly pathway, and Wnt signaling pathway [1,2,7]. Genetic models, especially KO/CKO mouse models, have been instrumental in studying its functions.

In KO/CKO mouse models, conditional deletion of Emc3 in alveolar type 2 epithelial (AT2) cells rescued alveolar remodeling defects associated with the SFTPCI73T mutation, reversing disruption of vesicle trafficking and mitochondrial dysfunction [1]. In mouse embryonic mesoderm, Emc3 deficiency led to reduced organ size, spindle assembly defects, and apoptosis due to cell cycle arrest at G2/M [2]. In intestinal epithelium, Emc3 deletion decreased mucus production, Paneth cell population, and led to gut microbial dysbiosis and increased susceptibility to colitis [3]. In the retina, loss of Emc3 caused retinal rosette degeneration, mislocalization of cell-junction and polarity molecules, and loss of visual function despite increased photoreceptor cell production [4]. In endothelial cells, postnatal Emc3 deletion retarded retinal vascular development by affecting the FZD4/WNT signaling axis [7]. In intestinal epithelial cells, Emc3 deletion led to decreased levels of membrane proteins like CFTR and impaired calcium mobilization [6].

In conclusion, Emc3 is essential for maintaining normal physiological functions in multiple tissues and organs. KO/CKO mouse models have revealed its role in diseases such as interstitial lung disease, and in processes like cell cycle regulation, intestinal and retinal homeostasis, and angiogenesis. These findings provide potential therapeutic targets for related diseases [1,2,3,4,6,7].

References:

1. Tang, Xiaofang, Wei, Wei, Sun, Yuqing, Lin, Xinhua, Whitsett, Jeffrey A. 2024. EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease. In The Journal of clinical investigation, 134, . doi:10.1172/JCI173861. https://pubmed.ncbi.nlm.nih.gov/39405113/

2. Tang, Xiaofang, Wei, Wei, Snowball, John M, Lin, Xinhua, Whitsett, Jeffrey A. 2022. EMC3 regulates mesenchymal cell survival via control of the mitotic spindle assembly. In iScience, 26, 105667. doi:10.1016/j.isci.2022.105667. https://pubmed.ncbi.nlm.nih.gov/36624844/

3. Huang, Meina, Yang, Li, Jiang, Ning, Zhao, Bing, Lin, Xinhua. 2021. Emc3 maintains intestinal homeostasis by preserving secretory lineages. In Mucosal immunology, 14, 873-886. doi:10.1038/s41385-021-00399-2. https://pubmed.ncbi.nlm.nih.gov/33785873/

4. Cao, Xiaowen, An, Jianhong, Cao, Yuqing, Lin, Xinhua, Zhou, Xiangtian. . EMC3 Is Essential for Retinal Organization and Neurogenesis During Mouse Retinal Development. In Investigative ophthalmology & visual science, 62, 31. doi:10.1167/iovs.62.2.31. https://pubmed.ncbi.nlm.nih.gov/33605987/

5. Tang, Xiaofang, Snowball, John M, Xu, Yan, Lin, Xinhua, Whitsett, Jeffrey A. 2017. EMC3 coordinates surfactant protein and lipid homeostasis required for respiration. In The Journal of clinical investigation, 127, 4314-4325. doi:10.1172/JCI94152. https://pubmed.ncbi.nlm.nih.gov/29083321/

6. Penrod, Sarah, Tang, Xiaofang, Moon, Changsuk, Naren, Anjaparavanda P, Huang, Yunjie. 2024. EMC3 is critical for CFTR function and calcium mobilization in the mouse intestinal epithelium. In American journal of physiology. Gastrointestinal and liver physiology, 328, G72-G82. doi:10.1152/ajpgi.00066.2024. https://pubmed.ncbi.nlm.nih.gov/39641142/

7. Yang, Mu, Li, Shujin, Liu, Wenjing, Yang, Zhenglin, Zhu, Xianjun. 2021. The ER membrane protein complex subunit Emc3 controls angiogenesis via the FZD4/WNT signaling axis. In Science China. Life sciences, 64, 1868-1883. doi:10.1007/s11427-021-1941-7. https://pubmed.ncbi.nlm.nih.gov/34128175/