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, 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.

This article is related to:

MIST1 and PTF1 Collaborate in Feed-Forward Regulatory Loops That Maintain the Pancreatic Acinar Phenotype in Adult Mice

MIST1 and PTF1 Collaborate in Feed-Forward Regulatory Loops That Maintain the Pancreatic Acinar Phenotype in Adult Mice

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ACKNOWLEDGMENTS

We thank the Purdue University Center for Cancer Research Transgenic Mouse Core Facility (supported by P30 CA023168) for producing the genetically engineered mouse strains and the mouse embryo fibroblasts used in this study.

This work was supported by grants to S.F.K. (NIH DK55489 and NIH CA124586), a grant from the Indiana Clinical and Translational Sciences Institute (ICTSI 22-808-25), a Purdue Research Foundation Fellowship to D.A.H., and a grant to R.J.M. (NIH DK61220).

We declare that we have no conflicts of interest.

D.A.H., K.M.S., and A.K. designed, performed, and analyzed experiments; T.G.D., C.Q.H., and R.J.M. designed and performed ChIP-Seq experiments; M.J. and A.C.A.-P. analyzed data; A.-H.L. provided cellular reagents; D.A.H. and S.F.K. wrote the manuscript.

Notes

For a companion article on this topic, see doi:10.1128/MCB.00370-16.