IRE1, an ER-localized transmembrane-RNase, plays a central role in ER stress response. Upon ER stress, IRE1 induces various adaptive genes through the processing of mRNA encoding the transcription factor XBP1. Moreover, it was recently reported that in fly IRE1 attenuates the expression of several genes by cleaving mRNAs, but it has been unclear whether such a mechanism also exists in mammal. In this study, we searched for IRE1 alpha-cleaved mRNAs in mammalian cells and identified human CD59 (complement defense 59) mRNA as a novel cleavage target. In addition, the expression of CD59 was significantly attenuated by overexpression of IRE1 alpha or ER stress. These results suggest that IRE1 alpha-mediated mRNA cleavage functions even in mammals as a common system to regulate gene expression. (c) 2007 Elsevier Inc. All rights reserved.