TRAM1, short for translocating chain-associated membrane protein 1, is an ER-resident multispanning membrane protein. It is involved in the translocation of nascent polypeptides and functions as a sorting adaptor of TLR4. It may support ER protein import by modulating the phospholipid bilayer near the lateral gate of the Sec61-channel [3]. It also participates in multiple biological processes related to various diseases.

In microglia, TRAM1 promotes M1 polarization. Its expression is highly induced in LPS/interferon-γ-stimulated cells, and transfection enhances M1 polarization while silencing inhibits the expression of M1-related genes [2]. In AR42J rat pancreatic acinar cells, knockdown of TRAM1 leads to hyperactivation of ER-stress-related proteins and downstream apoptosis pathway, suggesting it protects cells from caerulein-induced acute pancreatitis [4]. In HepG2 cells, depletion of TRAM1 causes hyperactivation of certain proteins and JNK pathway, indicating it protects against palmitate-induced insulin resistance [5]. In the context of SARS-CoV-2, the REEP5/TRAM1 complex binds NSP3 and promotes virus replication [1]. Also, in rats, TRAM1 increases in dorsal root ganglion and spinal cord neurons after chronic constriction injury, and its knockdown alleviates pain response, suggesting its role in neuropathic pain [6].

In conclusion, TRAM1 has diverse biological functions. It plays important roles in processes like microglia polarization, cell protection against stress-induced injuries, virus replication, and neuropathic pain. Studies on TRAM1, especially through loss-of-function experiments, help us understand its functions in these disease-related biological processes, providing potential targets for therapeutic intervention.