TMEM45 protein family - Ancient residents of the cell endomembrane

The Transmembrane protein 45 (TMEM45) family comprises multi-pass transmembrane proteins that harbor the ancient DUF716 domain and are predominantly localized to the endomembrane system (endoplasmic reticulum, Golgi apparatus). In mammals, TMEM45 members exhibit highly tissue-specific expression patterns and their functions are tightly linked to endomembrane activities. TMEM45A directly binds prolyl-4-hydroxylase (P4HA1) to modulate extracellular matrix (ECM) synthesis, thereby contributing to fibrosis and corneal disorders. TMEM45B participates in the Golgi processing and trafficking of nociceptive signaling molecules and also influences viral replication. Another paralog, TEDDM1, is implicated in sperm maturation. Expression of TMEM45 proteins is stringently regulated by upstream signaling cascades including TGF-β1/Smad, hypoxia/HIF-1α, calcium signaling, and JAK2/STAT3. In turn, these proteins serve as regulatory nodes that modulate downstream pathways such as Jagged1/Notch, Rho/ROCK, unfolded protein response (UPR), NF-κB, AKT/mTOR, Wnt/β-catenin, DNA-damage repair, and apoptosis. This review integrates current knowledge on the tissue distribution and upstream/downstream signaling networks of TMEM45 proteins to clarify endomembrane protein function and provide new perspectives on intracellular signal transduction mechanisms.