title: Zhangfei/CREB-ZF - a potential regulator of the unfolded protein response.
abstract: 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.
authors.affiliation: Department of Microbiology,Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan,Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Noreen
authors.initials: N
authors.lastname: Rapin
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Ying
authors.forename: Erika
authors.initials: E
authors.lastname: Shklanka
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Bodnarchuk
authors.forename: Valerie M K
authors.initials: VM
authors.lastname: Verge
authors.forename: Vikram
authors.initials: V
authors.lastname: Misra
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005455:Fluorescent Antibody Technique; D006360:Heat-Shock Proteins; D006801:Humans; D047468:Immunoprecipitation; D016350:Leucine Zippers; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000071701:Regulatory Factor X Transcription Factors; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D014709:Vero Cells; D000071717:X-Box Binding Protein 1
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C411104:CREBZF protein, human; C570110:Crebzf protein, rat; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605545:Xbp1 protein, rat; D019284:Thapsigargin; D046988:Proteasome Endopeptidase Complex