MIST1 links secretion and stress as both target and regulator of the unfolded protein response

David A. Hess, Katherine M. Strelau, Anju Karki, Mei Jiang, Ana C. Azevedo-Pouly, Ann Hwee Lee, Tye G. Deering, Chinh Q. Hoang, Raymond J. MacDonald, Stephen F. Konieczny

Research output: Contribution to journalArticle

12 Scopus citations

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, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

Original languageEnglish (US)
Pages (from-to)2931-2944
Number of pages14
JournalMolecular and Cellular Biology
Volume36
Issue number23
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hess, D. A., Strelau, K. M., Karki, A., Jiang, M., Azevedo-Pouly, A. C., Lee, A. H., Deering, T. G., Hoang, C. Q., MacDonald, R. J., & Konieczny, S. F. (2016). MIST1 links secretion and stress as both target and regulator of the unfolded protein response. Molecular and Cellular Biology, 36(23), 2931-2944. https://doi.org/10.1128/MCB.00366-16