The CrebA/Creb3-like transcription factors are major and direct regulators of secretory capacity

Department of Cell Biology, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 11/2010; 191(3):479-92. DOI: 10.1083/jcb.201004062
Source: PubMed


Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary, and mammary glands. How secretory capacity is selectively up-regulated in specialized secretory cells is unknown. Here, we find that the CrebA/Creb3-like family of bZip transcription factors functions to up-regulate expression of both the general protein machinery required in all cells for secretion and of cell type-specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also up-regulates expression of genes encoding cell type-specific secreted components. Finally, we found that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to up-regulate the secretory pathway in nonsecretory cell types.

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Available from: Rebecca M Fox, Jan 24, 2014
    • "contains sequence fragments from flanking noncoding regions of cyclic-AMP response element binding protein A (CrebA), a gene that regulates secretory capacity in Drosophila (Fox et al. 2010). We used CrebA-GAL4 to induce PEBme knockdown in males and examined PMP formation in their mates. "
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    ABSTRACT: Within the mated reproductive tracts of females of many taxa, seminal fluid proteins (SFPs) coagulate into a structure known as the mating plug (MP). MPs have diverse roles, including preventing female remating, altering female receptivity post-mating, and being necessary for mated females to successfully store sperm. The Drosophila melanogaster MP, which is maintained in the mated female for several hours post-mating, is comprised of a posterior MP (PMP) that forms quickly after mating begins and an anterior MP (AMP) that forms later. The PMP is composed of seminal proteins from the ejaculatory bulb (EB) of the male reproductive tract. To examine the role of the PMP protein PEBme in D. melanogaster reproduction, we identified an EB GAL4 driver and used it to target PEBme for RNAi knockdown. PEBme knockdown in males compromised PMP coagulation in their mates and resulted in a significant reduction in female fertility, adversely affecting post-mating uterine conformation, sperm storage, mating refractoriness, egg-laying and progeny generation. These defects resulted from the inability of females to retain the ejaculate in their reproductive tracts after mating. The uncoagulated MP impaired uncoupling by the knockdown male and, when he ultimately uncoupled, the ejaculate was pulled out of the female. Thus PEBme and MP coagulation are required for optimal fertility in D. melanogaster. Given the importance of the PMP for fertility, we identified additional MP proteins by mass spectrometry and found fertility functions for two of them. Our results highlight the importance of the MP and the proteins that comprise it in reproduction, and suggest that in Drosophila, the PMP is required to retain the ejaculate within the female reproductive tract to ensure the storage of sperm by mated females. Copyright © 2015, The Genetics Society of America.
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    • "C. elegans contains three bZIP transcription factors. Although the degree of homology is less than those in the mammalian family, these proteins are related most closely to ATF6, OASIS and Luman (Shen et al. 2005; Fox et al. 2010). In Drosophila, two bZIP transcription factors are related most closely to ATF6 and OASIS (Fox et al. 2010). "
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    ABSTRACT: Eukaryotic cells can adapt to endoplasmic reticulum (ER) dysfunction by producing diverse signals from the ER to the cytosol or nucleus. These signaling pathways are collectively known as the unfolded protein response (UPR). The canonical branches of the UPR are mediated by three ER membrane-bound proteins: double-stranded RNA-dependent protein kinase (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6). These ER stress transducers basically play important roles in cell survival after ER stress. Recently, novel types of ER stress transducers that share a region of high sequence similarity with ATF6 have been identified. They have a transmembrane domain, which allows them to associate with the ER, and possess a transcription-activation domain and a basic leucine zipper (bZIP) domain. These membrane-bound bZIP transcription factors include OASIS, BBF2H7 CREBH, CREB4 and Luman, and are collectively referred to as OASIS family members. Despite their structural similarities with ATF6, differences in activating stimuli and tissue distribution indicate specialized functions of each member on regulating UPR signaling in specific organs and tissues. One of them, OASIS, is expressed preferentially in astrocytes in the central nervous system (CNS). OASIS temporally regulates the differentiation from neural precursor cells into astrocytes to promote the expression of Glial Cell Missing 1 through dynamic interactions among OASIS family members followed by accelerating demethylation of the Gfap promoter. This review is a summary of our current understanding of the physiological functions of OASIS in the CNS.
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    • "Mutations that perturb normal secretory function in Drosophila have been shown to have profound effects on larval cuticle development [13,14,26]. Therefore, we examined the cuticles of KdelR mutants to ask if KDEL receptor loss-of-function affects cuticle development. "
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    ABSTRACT: Core components of the secretory pathway have largely been identified and studied in single cell systems such as the budding yeast S. cerevisiae or in mammalian tissue culture. These studies provide details on the molecular functions of the secretory machinery; they fail, however, to provide insight into the role of these proteins in the context of specialized organs of higher eukaryotes. Here, we identify and characterize the first loss-of-function mutations in a KDEL receptor gene from higher eukaryotes. Transcripts from the Drosophila KDEL receptor gene KdelR - formerly known as dmErd2 - are provided maternally and, at later stages, are at elevated levels in several embryonic cell types, including the salivary gland secretory cells, the fat body and the epidermis. We show that, unlike Saccharomyces cerevisiae Erd2 mutants, which are viable, KdelR mutations are early larval lethal, with homozygous mutant animals dying as first instar larvae. KdelR mutants have larval cuticle defects similar to those observed with loss-of-function mutations in other core secretory pathway genes and with mutations in CrebA, which encodes a bZip transcription factor that coordinately upregulates secretory pathway component genes in specialized secretory cell types. Using the salivary gland, we demonstrate a requirement for KdelR in maintaining the ER pool of a subset of soluble resident ER proteins. These studies underscore the utility of the Drosophila salivary gland as a unique system for studying the molecular machinery of the secretory pathway in vivo in a complex eukaryote.
    Preview · Article · Oct 2013 · PLoS ONE
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