XBP1 MRNA Splicing Triggers an Autophagic Response in Endothelial Cells Through BECLIN-1 Transcriptional Activation

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2012 Nov 28

PMID 23184933

Citations 150

Authors

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

Affiliations

Soon will be listed here.

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 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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