Activation of sterol regulatory element-binding protein by the caspase Drice in Drosophila larvae.
ABSTRACT 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.
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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 · 12.64 Impact Factor
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ABSTRACT: The sterol regulatory element binding protein (SREBP) pathway plays a central role in the global regulation of lipid homeostasis. SREBPs are membrane-bound transcription factors whose proteolytic activation is regulated by cellular lipid levels; when demand for lipid rises, SREBP travels from the endoplasmic reticulum to the Golgi apparatus where it is cleaved by two distinct proteases. Cleavage releases the transcription factor domain of SREBP from the membrane-bound precursor and transcription of its target genes consequently rises. Previously, we isolated Drosophila mutants null for dsrebp and others lacking site-2 protease (ds2p), the second of two Golgi-resident proteases that cleave dSREBP. dScap is a protein needed to escort dSREBP from the ER to the Golgi apparatus. We recently characterized the phenotypes of dscap mutants as well. Here, we describe additional details of phenotypes arising from the inability to activate SREBP appropriately.Fly 01/2010; 5(1):3-6. DOI:10.4161/fly.5.1.13475 · 1.48 Impact Factor
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ABSTRACT: The escort factor Scap is essential in mammalian cells for regulated activation of sterol regulatory element binding proteins (SREBPs). SREBPs are membrane-bound transcription factors. Cells lacking Scap cannot activate SREBP. They are therefore deficient in the transcription of numerous genes involved in lipid synthesis and uptake; they cannot survive in the absence of exogenous lipid. Here we report that, in contrast to mammalian cells, Drosophila completely lacking dscap are viable. Flies lacking dscap emerge at approximately 70% of the expected rate and readily survive as homozygous stocks. These animals continue to cleave dSREBP in some tissues. Transcription of dSREBP target genes in dscap mutant larvae is reduced compared to wild type. It is greater than in mutants lacking dSREBP and remains responsive to dietary lipids in dscap mutants. Flies lacking dscap do not require the caspase Drice to activate dSREBP. This contrasts with ds2p mutants. ds2p encodes a protease that releases the transcription factor domain of dSREBP from the membrane. Larvae doubly mutant for dscap and ds2p exhibit phenotypes similar to those of ds2p single mutants. Thus, dScap and dS2P, essential components of the SREBP activation machinery in mammalian cells, are dispensable in Drosophila owing to different compensatory mechanisms.Genetics 02/2010; 185(1):189-98. DOI:10.1534/genetics.110.114975 · 4.87 Impact Factor