Transmembrane Protein 214 (TMEM214) mediates endoplasmic reticulum stress-induced caspase 4 enzyme activation and apoptosis

Endoplasmic reticulum (ER) stress caused by excessive aggregation of misfolded proteins induces Apoptosis. Although ER stress-induced Apoptosis has been implicated in many diseases, the detailed mechanisms are not well understood. Here, we identified human transmembrane protein 214 (TMEM214) as a critical mediator of ER stress-induced Apoptosis. Overexpression of TMEM214 induced Apoptosis, whereas knockdown of TMEM214 inhibited ER stress-induced Apoptosis. TMEM214 was localized on the outer membrane of the ER and constitutively associated with procaspase 4, which was also critical for ER stress-induced Apoptosis. TMEM214-induced Apoptosis was abolished by a dominant negative mutant of procaspase 4, whereas Caspase 4-induced Apoptosis was inhibited by knockdown of TMEM214. Furthermore, knockdown of TMEM214 inhibited the activation and cleavage of procaspase 4 by impairing its recruitment to the ER. Our findings suggest that TMEM214 is essential for ER stress-induced Apoptosis by acting as an anchor for recruitment of procaspase 4 to the ER and its subsequent activation.

Apoptosis; Caspase; Caspase 4; Cell Signaling; ER Stress; TMEM214; Unfolded Protein Response.