Abstract
Intracellular trafficking is a key mechanism that regulates cell fate by participating in pro‐death or pro‐survival signaling. A soluble N‐ethylmaleimide sensitive factor (NSF) attachment protein alpha (αSNAP) is well‐known component of vesicle trafficking machinery. αSNAP increases cell resistance to cytotoxic stimuli, although mechanisms of its pro‐survival function remain poorly understood. In this study, we found that either siRNA‐mediated knockdown, or overexpression of dominat negative form of αSNAP induced apoptosis in several types of epithelial cells. This apoptosis was not caused by activation of the major pro‐death regulators Bax and p53 and was independent of a key αSNAP binding partner, NSF. Instead, death of αSNAP‐depleted cells was accompanied by down‐regulation of the anti‐apoptotic Bcl‐2 protein; it was mimicked by inhibition and attenuated by overexpression of Bcl‐2. αSNAP depletion resulted in impaired Endoplasmic Reticulum (ER) to Golgi trafficking and Golgi fragmentation. Furthermore, pharmacological disruption of Golgi/ER with brefeldin A and eeyarestatin or depletion of ER‐Golgi associated AAA‐ATPase p97 decreased Bcl‐2 level and triggered cell apoptosis. These results reveal a novel role for αSNAP in regulating epithelial cell survival. Supported by NIH grants DK083968 and DK084953 to AII.
Published Version
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