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A CREBZF/Zhangfei isoform activates CHOP during prolonged cellular stress

Li, Y.; Yip, W. K.; Penney, J.; Taylor, T.; Zhang, Y.; Zeng, M.; Audas, T. E.; Lu, R.

2022-10-11 molecular biology
10.1101/2022.10.10.511668 bioRxiv
Show abstract

The basic leucine zipper transcription factor CREBZF (Zhangfei or ZF) was identified through its interaction with Herpes Simplex Virus-1 related cellular protein HCF-1. CREBZF has been implicated in cellular stress responses through its interaction with other proteins, such as CREB3/Luman and ATF4. Here we investigated the production of four CREBZF isoforms, which arise from translational initiation of a downstream AUG at codon 83, and mRNA alternative splicing that adds an IFFFR pentapeptidyl tail to the C-terminus. We found that in addition to transcriptional activation, the short-tailed CREBZF (stZF) isoform was specifically induced by prolonged ER stress treatment. This stZF isoform is a potent transcriptional activator of the pro-apoptotic protein CHOP. Overexpression of stZF activates transcription of CHOP through a CCAAT enhancer binding protein (C/EBP)-ATF site, and promotes apoptosis. We propose that 1) CREBZF is a key component of the Integrated Stress Response (ISR); 2) stZF is essential for the role of CREBZF in inducing CHOP and promoting cell death upon prolonged cellular stress.

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