During larval development in Drosophila melanogaster, transcriptional activation of target genes by sterol regulatory element-binding protein (dSREBP) is essential for survival. In all cases studied to date, activation of SREBPs requires sequential proteolysis of the membrane-bound precursor by site-1 protease (S1P) and site-2 protease (S2P). Cleavage by S2P, within the first membrane-spanning helix of SREBP, releases the transcription factor. In contrast to flies lacking dSREBP, flies lacking dS2P are viable. The Drosophila effector caspase Drice cleaves dSREBP, and cleavage requires an Asp residue at position 386, in the cytoplasmic juxtamembrane stalk. The initiator caspase Dronc does not cleave dSREBP, but animals lacking dS2P require both drice and dronc to complete development. They do not require Dcp1, although this effector caspase also can cleave dSREBP in vitro. Cleavage of dSREBP by Drice releases the amino-terminal transcription factor domain of dSREBP to travel to the nucleus where it mediates the increased transcription of target genes needed for lipid synthesis and uptake. Drice-dependent activation of dSREBP explains why flies lacking dS2P are viable, and flies lacking dSREBP itself are not.
"A possible function of DIAP1 and Ice to regulate tracheal membrane involves SREBP/HLH106, the sterol response element binding protein that is a transcription factor required for production of membrane lipid. Interestingly, SREBP is translated as a plasma membrane-bound form that is cleaved by Ice to liberate the functional transcription factor . In the tracheal system, non-apoptotic Ice activity may activate SREBP to promote membrane expansion. "
[Show abstract][Hide abstract] ABSTRACT: Precise control of epithelial tube size is critical for organ function, yet the molecular mechanisms remain poorly understood. Here, we examine the roles of cell growth and a highly conserved organ growth regulatory pathway in controlling the dimensions of the Drosophila tracheal (airway) system, a well-characterized system for investigating epithelial tube morphogenesis. We find that tracheal tube-size is regulated in unexpected ways by the transcription factor Yorkie (Yki, homolog of mammalian YAP and TAZ) and the Salvador/Warts/Hippo (SWH) kinase pathway. Yki activity typically promotes cell division, inhibits apoptosis, and can promote cell growth. However, reducing Yki activity in developing embryos increases rather than decreases the length of the major tracheal tubes, the dorsal trunks (DTs). Similarly, reduction of Hippo pathway activity, which antagonizes Yki, shortens tracheal DTs. yki mutations do not alter DT cell volume or cell number, indicating that Yki and the Hippo pathway regulate cell shape and apical surface area, but not volume. Yki does not appear to act through known tracheal pathways of apical extracellular matrix, septate junctions (SJs), basolateral or tubular polarity. Instead, the Hippo pathway and Yki appear to act downstream or in parallel to SJs because a double mutant combination of an upstream Hippo pathway activator, kibra, and the SJ component sinu have the short tracheal phenotype of a kibra mutant. We demonstrate that the critical target of Yki in tube size control is Drosophila Inhibitor of Apoptosis 1 (DIAP1), which in turn antagonizes the Drosophila effector caspase, Ice. Strikingly, there is no change in tracheal cell number in DIAP1 or Ice mutants, thus epithelial tube size regulation defines new non-apoptotic roles for Yki, DIAP1 and Ice.
PLoS ONE 07/2014; 9(7):e101609. DOI:10.1371/journal.pone.0101609 · 3.23 Impact Factor
"The survival rate of heterozygous offspring of homozygous female flies was not reported in this study, leaving open the possibility that dS2P may function as a maternal-zygotic effect gene. However, in contrast to the nonredundant function of S1P in mice, the caspase drICE can partially compensate for dS2P deficiency in Drosophila, thus permitting a significant proportion of homozygous fly embryos derived from homozygous mothers to survive to adulthood (Amarneh et al. 2009). Notably, maternal effect embryonic lethality of homozygous mutant flies was completely rescued by supplementation of the embryo culture medium with fatty acids (Matthews et al. 2009). "
[Show abstract][Hide abstract] ABSTRACT: The site 1 protease, encoded by Mbtps1, mediates the initial cleavage of site 2 protease substrates, including sterol regulatory element binding proteins and CREB/ATF transcription factors. We demonstrate that a hypomorphic mutation of Mbtps1 called woodrat (wrt) caused hypocholesterolemia, as well as progressive hypopigmentation of the coat, that appears to be mechanistically unrelated. Hypopigmentation was rescued by transgenic expression of wild-type Mbtps1, and reciprocal grafting studies showed that normal pigmentation depended upon both cell-intrinsic or paracrine factors, as well as factors that act systemically, both of which are lacking in wrt homozygotes. Mbtps1 exhibited a maternal-zygotic effect characterized by fully penetrant embryonic lethality of maternal-zygotic wrt mutant offspring and partial embryonic lethality (~40%) of zygotic wrt mutant offspring. Mbtps1 is one of two maternal-zygotic effect genes identified in mammals to date. It functions nonredundantly in pigmentation and embryogenesis.
"The mechanism of dSREBP proteolysis mirrors that of mammalian cells, with dSCAP facilitating ER-to-Golgi transport and interaction of dSREBP with homologs of S1P and S2P. Interestingly, studies of dS2P- null flies revealed an alternative pathway for dSREBP activation that requires the caspase Drice and permits larval development in the absence of normal Site-2 protease cleavage (Amarneh et al. 2009; Matthews et al. 2009). These data indicate that dSREBP functions in the D. melanogaster fat body and gut to promote fatty acid synthesis essential for development. "
[Show abstract][Hide abstract] ABSTRACT: Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors that are conserved from fungi to humans and are defined by two key features: a signature tyrosine residue in the DNA-binding domain, and a membrane-tethering domain that is a target for regulated proteolysis. Recent studies including genome-wide and model organism approaches indicate SREBPs coordinate cellular lipid metabolism with other cellular physiologic processes. These functions are broadly related as cellular adaptation to environmental changes ranging from nutrient fluctuations to toxin exposure. This review integrates classic features of the SREBP pathway with newer information regarding the regulation and sensing mechanisms that serve to assimilate different cellular physiologic processes for optimal function and growth.
Genes & development 11/2009; 23(22):2578-91. DOI:10.1101/gad.1854309 · 10.80 Impact Factor
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