Zhangfei/CREB-ZF - a potential regulator of the unfolded protein response

• Published in: PloS one 2013-10, Vol.8 (10), p.e77256
• Main Authors: Zhang, Rui, Rapin, Noreen, Ying, Zhengxin, Shklanka, Erika, Bodnarchuk, Timothy W, Verge, Valerie M K, Misra, Vikram
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Basic-Leucine Zipper Transcription Factors - metabolism; Calcium; Calcium ionophores; Cell Line, Tumor; Cercopithecus aethiops; Cyclic AMP response element-binding protein; DNA binding proteins; DNA-Binding Proteins - metabolism; Endoplasmic reticulum; Experiments; Fluorescent Antibody Technique; Gene expression; Genes; Heat-Shock Proteins; Herpes viruses; Homeostasis; Humans; Immunoprecipitation; Kinases; Leucine; Leucine zipper proteins; Leucine Zippers; Male; Membrane Proteins - metabolism; Multiple sclerosis; Neurosciences; Overloading; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Binding - drug effects; Protein folding; Protein synthesis; Proteins; Proteolysis - drug effects; Rats; Rats, Wistar; Regulatory Factor X Transcription Factors; Regulatory sequences; Ribonucleic acid; RNA; Sensory neurons; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; siRNA; Thapsigargin; Thapsigargin - pharmacology; Transcription factors; Transcription Factors - metabolism; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Tumors; Unfolded Protein Response - drug effects; Unfolded Protein Response - genetics; Vero Cells; Veterinary colleges; Veterinary medicine; X-Box Binding Protein 1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0077256

Cells respond to perturbations in the microenvironment of the endoplasmic reticulum (ER), and to the overloading of its capacity to process secretory and membrane-associate proteins, by activating the Unfolded Protein Response (UPR). Genes that mediate the UPR are regulated by three basic leucine-zipper (bLZip) motif-containing transcription factors - Xbp1s, ATF4 and ATF6. A failure of the UPR to achieve homeostasis and its continued stimulation leads to apoptosis. Mechanisms must therefore exist to turn off the UPR if it successfully restores normalcy. The bLZip protein Zhangfei/CREBZF/SMILE is known to suppress the ability of several, seemingly structurally unrelated, transcription factors. These targets include Luman/CREB3 and CREBH, ER-resident bLZip proteins known to activate the UPR in some cell types. Here we show that Zhangfei had a suppressive effect on most UPR genes activated by the calcium ionophore thapsigargin. This effect was at least partially due to the interaction of Zhangfei with Xbp1s. The leucine zipper of Zhangfei was required for this interaction, which led to the subsequent proteasomal degradation of Xbp1s. Zhangfei suppressed the ability of Xbp1s to activate transcription from a promoter containing unfolded protein response elements and significantly reduced the ability to Xbp1s to activate the UPR as measured by RNA and protein levels of UPR-related genes. Finally, specific suppression of endogenous Zhangfei in thapsigargin-treated primary rat sensory neurons with siRNA directed to Zhangfei transcripts, led to a significant increase in transcripts and proteins of UPR genes, suggesting a potential role for Zhangfei in modulating the UPR.