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

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

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

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 3ß (LC3-ßII). Endostatin activated autophagic gene expression through XBP1 mRNA splicing in an inositol-requiring enzyme 1a (IRE1a)-dependent manner. Knockdown of XBP1 or IRE1a 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 LC3ß 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.
Original languageEnglish
Pages (from-to)859-72
Number of pages14
JournalJournal of Biological Chemistry
Volume288
Issue number2
Early online date26 Nov 2012
DOIs
Publication statusPublished - 11 Jan 2013

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    Margariti, A., Li, H., Chen, T., Martin, D., Vizcay-Barrena, G., Alam, S., Karamariti, E., Xiao, Q., Zampetaki, A., Zhang, Z., Wang, W., Jiang, Z., Gao, C., Ma, B., Chen, Y-G., Cockerill, G., Hu, Y., Xu, Q., & Zeng, L. (2013). XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. Journal of Biological Chemistry, 288(2), 859-72. https://doi.org/10.1074/jbc.M112.412783