TMEM214Mediates ER Stress-induced Caspase-4Activation And Apoptosis

Apoptosis, also known as programmed cell death, is characterized by the morpholosical and biochemical changes of cells, and plays a central role in embryonic development, removal of damaged cells, and maintenance of cell homeostasis. Dysfunction of apoptosis may cause severe deseases, such as tumorigenesis and immune disorder. So far, two different apoptotic pathways have been identified:the external pathway which is induced by the death receptors on cell surface, and the internal pathway which is induced by mitochondrial damage or ER stress. In this study, we identified an ER protein, TMEM214, as a critical mediator of ER stress-induced apoptosis.The efficient functioning of the endoplasmic reticulum (ER) is essential for most cellular activities. Conditions that interfere with ER function lead to the accumulation and aggregation of unfold proteins which cause severe ER stress. ER transmembrane receptors detect the onset of ER stress and initiate the unfolded protein response (UPR) to restore normal ER function. However, prolonged and unresolved ER stresss results in apoptosis and the detailed mechanism is not well understood. Previous studies have suggestted that ER stress triggers apoptosis through three pathways, including CHOP induction, JNK phosphorylation and caspase activation. CHOP upregulates expression of proapoptotic genes such as:GADD34and DR5, while JNK activates the proapoptotic transcription factor c-Jun. Our findings indicated that TMEM214mediated ER stress-induced apoptosis by regulating the activation of caspase-4, and had no marker effects on ER stress-induced CHOP induction and JNK phosphorylation. Overexpression of TMEM214induced apoptosis, whereas knockdown of TMEM214inhibited ER stress, but not death receptor-or mitochondrial damage-induced apoptosis. TMEM214was localized on the outer membrane of ER and constitutively associated with procaspase-4, another protein that was critical for ER stress-induced apoptosis. Interestingly, neither overexpression nor knockdown of TMEM214had any effect on ER stress-induced expression of CHOP or activation of JNK. In contrast, TMEM214-induced apoptosis was abolished by a dominant negative mutant of caspase-4, whereas caspase-4-induced apoptosis was inhibited by knockdown of TMEM214. Furthermore, knockdown of TMEM214inhibited the activation and cleavage of procaspase-4by impairing its recruitment to the ER. Our findings suggest that TMEM214is essential for ER stress-induced apoptosis by acting as an anchor for recruitment of procaspase-4to the ER and its subsequent activation, and provide important insight to the molecular mechanisms of ER stress-induced apoptosis.