Emc3, also known as TMEM111, is a subunit of the endoplasmic reticulum membrane complex (EMC). The EMC is involved in processes like the synthesis and quality control of multi-transmembrane domain membrane proteins. Emc3 provides a hydrophilic vestibule for substrate insertion. It is crucial for multiple biological processes, including surfactant homeostasis, cell cycle regulation, and tissue development [1,2,3,4,5,6]. Genetic models, especially KO/CKO mouse models, have been instrumental in studying its functions.

Conditional deletion of Emc3 in alveolar type 2 (AT2) cells in a knock-in mouse model phenocopying the SFTPCI73T mutation rescued alveolar remodeling defects, reversed vesicle trafficking disruption, and mitochondrial dysfunction associated with the mutation [1]. In mouse embryonic mesoderm, Emc3 deficiency led to reduced organ size, spindle assembly defects, and apoptosis due to its role in regulating the cell cycle [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 [4].

In conclusion, Emc3 plays essential roles in maintaining normal physiological functions across multiple tissues. KO/CKO mouse models have revealed its significance in diseases such as interstitial lung disease associated with the SFTPCI73T mutation, as well as in normal tissue development and homeostasis in the mesoderm, intestine, and retina. These studies contribute to understanding disease mechanisms and identifying potential therapeutic targets.