title: MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response.
abstract: Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly,Mist1gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding theXbp1promoter and repressingXbp1transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.
authors.affiliation: Department of Biological Sciences, Bindley Bioscience Center and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hess
authors.affiliation: Department of Biological Sciences, Bindley Bioscience Center and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Strelau
authors.affiliation: Department of Biological Sciences, Bindley Bioscience Center and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Anju
authors.initials: A
authors.lastname: Karki
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Azevedo-Pouly
authors.affiliation: Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ann-Hwee
authors.identifier: http://orcid.org/0000-0001-8569-9786
authors.initials: AH
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tye G
authors.initials: TG
authors.lastname: Deering
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chinh Q
authors.initials: CQ
authors.lastname: Hoang
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Raymond J
authors.identifier: http://orcid.org/0000-0002-8576-766X
authors.initials: RJ
authors.lastname: MacDonald
authors.affiliation: Department of Biological Sciences, Bindley Bioscience Center and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA sfk@purdue.edu.
authors.forename: Stephen F
authors.identifier: http://orcid.org/0000-0002-3281-3714
authors.initials: SF
authors.lastname: Konieczny