Tmx4, a member of the thioredoxin-related transmembrane protein family, is an N-glycosylated type I membrane protein that localizes to the endoplasmic reticulum (ER) [4]. It has a reductase activity, and its Trx-like domain can change redox state depending on cellular conditions [3]. Tmx4 is involved in several biological pathways such as protein folding in the ER [3], and in the regulation of nuclear envelope dynamics during ER stress [1,5].

In Tmx4-deficient mice, Tie2-Cre/TMX4fl/fl (deficient of hematopoietic and endothelial TMX4) and Pf4-Cre/TMX4fl/fl (deficient of platelet TMX4) showed prolonged tail bleeding times and reduced platelet thrombus formation. TMX4 deficiency inhibited platelet aggregation, integrin αIIbβ3 activation, P-selectin expression, phosphatidylserine exposure, and thrombin generation, indicating its role in platelet activation and thrombosis [2].

In conclusion, Tmx4 is crucial for maintaining normal cellular functions, especially in platelet-related thrombosis processes. The study of Tmx4-deficient mouse models has provided valuable insights into its role in platelet activation and thrombosis, which may help in developing new strategies for treating thrombotic diseases [2].

References:

1. Kucińska, Marika K, Fedry, Juliette, Galli, Carmela, Förster, Friedrich, Molinari, Maurizio. 2023. TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress. In Nature communications, 14, 3497. doi:10.1038/s41467-023-39172-3. https://pubmed.ncbi.nlm.nih.gov/37311770/

2. Zhao, Zhenzhen, Wang, Yucan, Yang, Aizhen, Wu, Depei, Wu, Yi. 2024. A novel role for thioredoxin-related transmembrane protein TMX4 in platelet activation and thrombus formation. In Journal of thrombosis and haemostasis : JTH, 23, 277-292. doi:10.1016/j.jtha.2024.09.007. https://pubmed.ncbi.nlm.nih.gov/39307246/

3. Sugiura, Yoshimi, Araki, Kazutaka, Iemura, Shun-ichiro, Hoseki, Jun, Nagata, Kazuhiro. 2010. Novel thioredoxin-related transmembrane protein TMX4 has reductase activity. In The Journal of biological chemistry, 285, 7135-42. doi:10.1074/jbc.M109.082545. https://pubmed.ncbi.nlm.nih.gov/20056998/

4. Roth, Doris, Lynes, Emily, Riemer, Jan, Simmen, Thomas, Ellgaard, Lars. 2009. A di-arginine motif contributes to the ER localization of the type I transmembrane ER oxidoreductase TMX4. In The Biochemical journal, 425, 195-205. doi:10.1042/BJ20091064. https://pubmed.ncbi.nlm.nih.gov/19811453/

5. Kucińska, Marika K, Molinari, Maurizio. 2024. Control of nuclear envelope dynamics during acute ER stress by LINC complexes disassembly and selective, asymmetric autophagy of the outer nuclear membrane. In Autophagy, 20, 1194-1196. doi:10.1080/15548627.2023.2299123. https://pubmed.ncbi.nlm.nih.gov/38153175/