Tmx4, a member of the thioredoxin-related transmembrane (TMX) protein family, is a type I transmembrane protein with a thioredoxin-like domain facing the endoplasmic reticulum (ER) lumen. It has reductase activity, which is crucial in several biological processes. Tmx4 is involved in the regulation of ER-related pathways, such as those related to protein folding, and has been associated with processes like platelet activation and thrombosis, as well as ER-stress responses in the nuclear envelope [2,3,4,5].

In platelet-related studies, Tmx4-deficient mice (Tie2-Cre/TMX4fl/fl and Pf4-Cre/TMX4fl/fl) 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 importance in platelet activation and thrombosis [3]. Regarding ER-stress, Tmx4-driven disassembly of the LINC complexes occurs upon acute ER stress, leading to ONM swelling. Asymmetric autophagy of the nuclear envelope, specifically micro-ONM-phagy, then restores the physiological distance between the inner and outer nuclear membranes upon stress resolution [1,5].

In conclusion, Tmx4 plays essential roles in platelet activation and thrombosis, as well as in maintaining the dynamics of the nuclear envelope during ER stress. The study of Tmx4 using gene-knockout mouse models has provided valuable insights into these biological functions, which are relevant to understanding platelet-related diseases and cellular responses to ER stress.