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, and is associated with pathways like the TLR4-related inflammatory response pathway [1,2].

TRAM1 has been studied in various disease-relevant contexts. In microglia, its over-expression promotes M1 polarization, while its silencing inhibits LPS/IFN-γ-induced M1-related gene expression, suggesting its role in CNS-related inflammatory disorders [1]. In AR42J cells, knockdown of TRAM1 leads to hyperactivation of ER stress-related proteins and increased secretion of pro-inflammatory mediators, indicating its protective role against caerulein-induced acute pancreatitis [3]. In HepG2 cells, depletion of TRAM1 causes hyperactivation of ER stress-related molecules and exacerbates palmitate-induced insulin resistance [4]. In the context of human cytomegalovirus, knockdown of TRAM1 in US2-and US11-expressing cells increases levels of class I heavy chains, showing its role in viral-mediated protein dislocation [5]. In rats with chronic constriction injury, intrathecal injection of TRAM1 siRNA alleviates neuropathic pain, suggesting its potential as a treatment target for chronic neuropathic pain [6].

In conclusion, TRAM1 plays essential roles in multiple biological processes, including immune cell polarization, ER-related stress responses, viral-host interactions, and pain regulation. Studies using loss-of-function models, such as siRNA-mediated knockdown, have revealed its significance in various disease conditions, including CNS disorders, pancreatitis, insulin resistance, viral-associated diseases, and neuropathic pain, providing potential therapeutic targets for these diseases.