CrebA increases secretory capacity through direct transcriptional regulation of the secretory machinery, a subset of secretory cargo, and other key regulators

Abstract

Specialization of many cells, including the acinar cells of the salivary glands and pancreas, milk‐producing cells of mammary glands, mucus‐secreting goblet cells, antibody‐producing plasma cells, and cells that generate the dense extracellular matrices of bone and cartilage, requires scaling up both secretory machinery and cell‐type specific secretory cargo. Using tissue‐specific genome‐scale analyses, we determine how increases in secretory capacity are coordinated with increases in secretory load in the Drosophila salivary gland (SG), an ideal model for gaining mechanistic insight into the functional specialization of secretory organs. Our findings show that CrebA, a bZIP transcription factor, directly binds genes encoding the core secretory machinery, including protein components of the signal recognition particle and receptor, ER cargo translocators, Cop I and Cop II vesicles, as well as the structural proteins and enzymes of these organelles. CrebA directly binds a subset of SG cargo genes and CrebA binds and boosts expression of Sage, a SG‐specific transcription factor essential for cargo expression. To further enhance secretory output, CrebA binds and activates Xbp1 and Tudor‐SN. Thus, CrebA directly upregulates the machinery of secretion and additional factors to increase overall secretory capacity in professional secretory cells; concomitant increases in cargo are achieved both directly and indirectly.

A Creb3-Like Transcription Factor Coordinates ER Function upon Food Intake to Regulate Lipid Metabolism

“…This indicates that CrebA activity is regulated by feeding. Additionally, an unbiased de novo search for sequence motifs in the CrebA-bound regions identified a robust enrichment for the known CrebA consensus sequence, further validating our ChIPseq results (Figure S2F) (Abrams and Andrew, 2005;Nitta et al, 2015;Johnson et al, 2020). Overall, our results highlight a rapid response of CrebA binding to its target genes upon refeeding.…”

“…There is evidence that Creb3L-family members transcriptionally regulate the Xbp1 gene (Johnson et al, 2020). In flies, ChIPseq data and transcriptional reporters in embryos indicate that Xbp1 transcription is directly activated by CrebA (Johnson et al, 2020). Further, we see CrebA bound to the Xbp1 promoter in adult heads (Figure S3C).…”

“…Accumulating evidence also points to feedback pathways between CrebA family members and the transcription factor Xbp1. There is evidence that Creb3L-family members transcriptionally regulate the Xbp1 gene (Johnson et al, 2020). In flies, ChIPseq data and transcriptional reporters in embryos indicate that Xbp1 transcription is directly activated by CrebA (Johnson et al, 2020).…”

Diverse cellular morphologies during lumen maturation in Anopheles gambiae larval salivary glands

“…4). Staining for CrebA (using rabbit antisera), a master regulator of secretory capacity (Abrams and Andrew, 2005; Fox and Andrew, 2015; Johnson et al ., 2020), was observed to variable degrees in all larval SG nuclei, along with localization of Sage (Fig. 4A; using rat antisera), an SG‐specific TF (Fox et al ., 2013).…”

The Ribb-osome: Ribbon boosts ribosomal protein gene expression to coordinate organ form and function

“…SGs are specified by the Hox protein Sex combs reduced (Scr) (Andrew et al, 1994;Panzer et al, 1992), working with Extradenticle (Exd) and Homothorax (Hth) (Henderson and Andrew, 2000). Scr, Exd and Hth activate a core set of transcription factors-Fork head (Fkh), Salivary gland-expressed bHLH (Sage), Cyclic-AMP response element binding protein A (CrebA), Senseless (Sens), and Huckebein (Hkb)-the actions of which regulate diverse cell physiological processes during SG tubulogenesis, while maintaining cell fate and priming secretory function 4 (Abrams and Andrew, 2005;Abrams et al, 2006;Fox et al, 2010;Fox et al, 2013;Johnson et al, 2020;Maruyama et al, 2011;Andrew, 2000a, 2002). A subset of these factors also controls the morphogenetic attributes of the SG tubulogenic program, e.g., cell invagination (Fkh) and tube elongation (Hkb) (Chung et al, 2017;Andrew, 2000a, b, 2002).…”