A CREBZF/Zhangfei isoform activates CHOP and induces apoptosis through a C/EBP-ATF element

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Li, Yu

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University of Guelph

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The basic leucine zipper (bZIP) transcription factor CREBZF/Zhangfei/ZF was identified through its interaction with the Herpes Simplex Virus-1 (HSV-1) related cellular protein HCF-1. In addition to the known CREBZF (the short form of CREBZF, sZF), we report here that this locus can produce three other isoforms by alternative transcript splicing, adding an IFFFR tail at the C-terminus, as well as by alternative translation initiation, adding 82 amino acids to the N-terminus. In ER stressor treated HeLa cells, we found that both CREBZF transcription and the protein level of 1ZF-IF3R isoform (the long ZF form with the IFFFR tail) were continuously induced and peaked at 24-36 h. Failure detection of sZF-IF3R is believed to be due to a fast turnover of the isoform, as the ER stressor tunicamycin or thapsigargin treatment reduced the half-life of sZF-IF3R from 6 h in untreated cells to 1.5 or 2.5 h, respectively. We found that only the IFFFR-tailed isoforms induced CHOP, with sZF-IF3R being the much more potent form. sZF-IF 3R induces CHOP through a C/EBP-ATF element, whose overexpression also promotes apoptosis, thus implicating sZF-IF3R in the CHOP-mediated apoptosis signaling pathway. We therefore propose a model in which the late onset expression of sZF-IF3R is essential for its function in the mammalian unfolded protein response (UPR). In the early stage of the UPR (4 h), the level of sZF-IFR is low and its activity is further repressed by protein degradation. This may allow time for other UPR branches to remedy the stress, thus favoring cell survival. In the late stage (24-36 h) when ER stress persists, the expression of IFFFR-tailed isoforms is induced. Once the accumulation of sZF-IF3R reaches a threshold, it may induce apoptosis through activation of the pro-apoptotic gene CHOP. Thus the time-dependent activation of sZF-IFR may provide cells with a mechanism to fine tune the delicate balance of cell survival and cell death during the UPR.

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CREBZF/Zhangfei isoform, CHOP, apoptosis, C/EBP-ATF element

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