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.

Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment

“…B,C). The sevenfold difference in DEGs between MIST1 and PTF1a cells is likely due to the functional nature of each transcription factor, where PTF1a is a master regulator for pancreatic acinar development while MIST1 is considered a scaling factor, augmenting specific transcription programs (Hess et al ., ; Jiang et al ., ; Kondratyeva et al ., ; Mills and Taghert, ; Tian et al ., ). Nonetheless, there was considerable overlap in DEGs regulated by both transcription factors, with 167 target genes induced by PTF1a and MIST1, representing 29% of the upregulated MIST1 targets (Fig.…”

“…Likewise, MIST1 promoted expression of the MIST1 target genes associated with the UPR pathway, including SEC61b , SEC62 , SEC63 , PERK , and DNAJc1 (Fig. B) (Direnzo et al ., ; Hess et al ., , ). Importantly, these data suggest that MIST1 can access target gene promoters in pancreatic cancer cells despite the inherent mutations, genomic instability, and altered epigenetic marks that are associated with these transformed cells (Deer et al ., ; Fazio et al ., ; Mehmood et al ., ; Pin et al ., ; Tan et al ., ).…”

“…Oncogenic KRAS is thought to be the primary driver of PDAC and readily transforms cells that have undergone acinar–ductal metaplasia (ADM), resulting in a dedifferentiated state where the proacinar basic helix‐loop‐helix (bHLH) transcription factor genes MIST1 and PTF1a are transcriptionally silenced (Adell et al ., ; Day et al ., ; Krah et al ., ; Rodolosse et al ., ; Guanglu Shi et al ., ; Zhu et al ., ). In healthy pancreata, MIST1 facilitates cell‐to‐cell communication, promotes acinar cell polarity, controls Ca 2+ flux, promotes unfolded protein response (UPR) homeostasis, aids in vesicle assembly, and is required for regulated exocytosis (Direnzo et al ., ; Garside et al ., ; Hess et al ., ; Jia et al ., ; Rukstalis et al ., ). PTF1a is necessary for pancreatic organogenesis and maintenance of gene expression networks associated with the production of a vast array of digestive hydrolases (Beres et al ., ; Direnzo et al ., ; Garside et al ., ; Hess et al ., ; Jia, ; Jiang et al ., ; Masui et al ., ).…”

“…In healthy pancreata, MIST1 facilitates cell‐to‐cell communication, promotes acinar cell polarity, controls Ca 2+ flux, promotes unfolded protein response (UPR) homeostasis, aids in vesicle assembly, and is required for regulated exocytosis (Direnzo et al ., ; Garside et al ., ; Hess et al ., ; Jia et al ., ; Rukstalis et al ., ). PTF1a is necessary for pancreatic organogenesis and maintenance of gene expression networks associated with the production of a vast array of digestive hydrolases (Beres et al ., ; Direnzo et al ., ; Garside et al ., ; Hess et al ., ; Jia, ; Jiang et al ., ; Masui et al ., ). Importantly, both MIST1 and PTF1a negatively regulate cell cycle progression by inducing p21 CIP1/WAF1 expression (Jia et al ., ; Rodolosse et al ., ).…”

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

“…Bhlha15) is a bHLH transcription factor present selectively in serous secretory cells, including pancreatic acinar cells (14,15). In the pancreas, Ptf1a and Mist1 are expressed selectively in acinar cells, and inactivation of either gene affects the differentiated acinar phenotype (16,17). Mist1-null pancreatic acinar cells have aberrant calcium signaling, reduced content of digestive enzymes, and decreased expression of critical genes of the secretory pathway, such as Rab genes (18)(19)(20).…”