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XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation

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Andriana Margariti, Hongling Li, Ting Chen, Daniel Martin, Gema Vizcay-Barrena, Saydul Alam, Eirini Karamariti, Qingzhong Xiao, Anna Zampetaki, Zhongyi Zhang, Wen Wang, Zhixin Jiang, Chan Gao, Benyu Ma, Ye-Guang Chen, Gillian Cockerill, Yanhua Hu, Qingbo Xu, Lingfang Zeng

Original languageEnglish
Pages (from-to)859-872
Number of pages14
JournalJournal of Biological Chemistry
Issue number2
Early online date26 Nov 2012
E-pub ahead of print26 Nov 2012
Published11 Jan 2013

King's Authors


Sustained activation of X-box-binding protein 1 (XBP1) results in endothelial cell (EC) apoptosis and atherosclerosis development. The present study provides evidence that XBP1 mRNA splicing triggered an autophagic response in ECs by inducing autophagic vesicle formation and markers of autophagy BECLIN-1 and microtubule-associated protein 1 light chain 3β (LC3-βII). Endostatin activated autophagic gene expression through XBP1 mRNA splicing in an inositol-requiring enzyme 1α (IRE1α)-dependent manner. Knockdown of XBP1 or IRE1α by shRNA in ECs ablated endostatin-induced autophagosome formation. Importantly, data from arterial vessels from XBP1 EC conditional knock-out (XBP1eko) mice demonstrated that XBP1 deficiency in ECs reduced the basal level of LC3β expression and ablated response to endostatin. Chromatin immunoprecipitation assays further revealed that the spliced XBP1 isoform bound directly to the BECLIN-1 promoter at the region from nt -537 to -755. BECLIN-1 deficiency in ECs abolished the XBP1-induced autophagy response, whereas spliced XBP1 did not induce transcriptional activation of a truncated BECLIN-1 promoter. These results suggest that XBP1 mRNA splicing triggers an autophagic signal pathway through transcriptional regulation of BECLIN-1.

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