The cargo receptor TMED9 modulates the unfolded protein response and affects ER stress induction

TMED9 (Trans-Membrane Emp24 Domain protein 9) is a cargo receptor shown to be involved in protein trafficking along the secretory pathway1,2. Recent findings point to the involvement of TMED9 in protein handling and quality control3. Specifically, this cargo receptor was shown to promote the retention of various misfolded proteins in post-ER compartments4. Earlier work from our lab has identified BRD4780, a small molecule that targets TMED9, promotes its removal and consequently induces misfolded protein clearance4. The goal of this study is to gain a better understanding of the normal function of TMED9 and its potential involvement in endoplasmic reticulum (ER) stress. To this end, we used genetic (Crispr-Cas9) and pharmacologic (BRD4780) manipulations to deprive cells from TMED9, and compared them to cells normally expressing the cargo receptor. Using these cellular model systems, we investigated the involvement of TMED9 in cell survival under normal conditions and upon ER stress induction. Our results demonstrate that while TMED9 had no effect on cell viability under normal settings, it altered cell fate determination upon ER stress induction. Interestingly, while TMED9 was shown to be pro-survival following Thapsigargin application, it facilitated apoptosis upon tunicamycin-indued ER stress. Importantly, the application of each of these stressors, resulted in an increase in TMED9 abundance. This study demonstrates an essential and complexed role of TMED9 in ER stress induction and introduces TMED9 as a potentially new post-ER modulator of the UPR network.