title: Luman contributes to brefeldin A-induced prion protein gene expression by interacting with the ERSE26 element.
abstract: The cellular prion protein (PrP) is essential for transmissible prion diseases, but its exact physiological function remains unclear. Better understanding the regulation of the human prion protein gene (PRNP) expression can provide insight into this elusive function. Spliced XBP1 (sXBP1) was recently shown to mediate endoplasmic reticulum (ER) stress-induced PRNP expression. In this manuscript, we identify Luman, a ubiquitous, non-canonical unfolded protein response (UPR), as a novel regulator of ER stress-induced PRNP expression. Luman activity was transcriptionally and proteolytically activated by the ER stressing drug brefeldin A (BFA) in human neurons, astrocytes, and breast cancer MCF-7 cells. Over-expression of active cleaved Luman (ΔLuman) increased PrP levels, while siRNA-mediated Luman silencing decreased BFA-induced PRNP expression. Site-directed mutagenesis and chromatin immunoprecipitation demonstrated that ΔLuman regulates PRNP expression by interacting with the ER stress response element 26 (ERSE26). Co-over-expression and siRNA-mediated silencing experiments showed that sXBP1 and ΔLuman both up-regulate ER stress-induced PRNP expression. Attempts to understand the function of PRNP up-regulation by Luman excluded a role in atorvastatin-induced neuritogenesis, ER-associated degradation, or proteasomal inhibition-induced cell death. Overall, these results refine our understanding of ER stress-induced PRNP expression and function.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Déry
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Andréa C
authors.initials: AC
authors.lastname: LeBlanc
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology; D001483:Base Sequence; D020126:Brefeldin A / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D011228:Prealbumin / Q000378:metabolism; D000072002:Prion Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics*; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000235:genetics; D000071717:X-Box Binding Protein 1 / Q000378:metabolism
chemical_list: C107941:CREB3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009842:Oligopeptides; D011228:Prealbumin; D000072002:Prion Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D020126:Brefeldin A; D000069059:Atorvastatin; D053148:Caspase 3; D053179:Caspase 7; C078846:epoxomicin