Alternative Processing of SREBP in Site 2 Protease and Scap Mutants During Larval Development in Drosophila Melanogaster
type: CreativeWork
description: Lipid metabolism is regulated by the membrane-bound transcription factor, sterol regulatory element binding protein (SREBP). SREBP requires release of the amino terminus from the membrane to activate transcription of genes involved in cholesterol and fatty acid synthesis. In response to low sterol levels, Scap escorts SREBP from the ER to the Golgi where it is cleaved by Site-1 and Site-2 proteases. The SREBP pathway is conserved in Drosophila despite these organisms being cholesterol auxotrophs. dSREBP is essential for activating genes involved in the uptake and synthesis of fatty acids which are required for rapid growth during larval development. I have demonstrated that processing of SREBP in Drosophila does not require the S2P or Scap, in contrast to the mammalian system. Flies lacking dS2P are viable and still process dSREBP. dS2P homozygotes were subviable, only emerging at 40% of the expected ratio. This phenotype can be rescued completely by supplementation with fatty acids. dSREBP activity was detected in the fat body of dS2P mutant larvae and to a lesser extent in the oenoctyes. Additionally, SREBP target genes were expressed at higher levels in dS2P homozygotes compared to dSREBP mutants, though less than wild type. dS2P mutants were viable due to alternative cleavage of dSREBP within the juxtamembrane region by the effector caspase, Drice. Flies lacking both dS2P and Drice, or the initiator caspase Dronc, exhibited an early larval lethality that could be rescued by lipid supplementation. Caspase cleavage was dependant upon the aspartic acid at residue 386 in dSREBP. dScap was not essential for larval growth or dSREBP processing in Drosophila. dScap mutants were relatively healthy, emerging at 70% of the expected numbers. dSREBP was actively cleaved in midgut and oenocytes, but significantly reduced in fat body. Levels of dSREBP mRNA and precursor were reduced in larvae lacking dScap, thus demonstrating that Drosophila SREBP is subject to feed-forward ac…
abstract: Lipid metabolism is regulated by the membrane-bound transcription factor, sterol regulatory element binding protein (SREBP). SREBP requires release of the amino terminus from the membrane to activate transcription of genes involved in cholesterol and fatty acid synthesis. In response to low sterol levels, Scap escorts SREBP from the ER to the Golgi where it is cleaved by Site-1 and Site-2 proteases. The SREBP pathway is conserved in Drosophila despite these organisms being cholesterol auxotrophs. dSREBP is essential for activating genes involved in the uptake and synthesis of fatty acids which are required for rapid growth during larval development. I have demonstrated that processing of SREBP in Drosophila does not require the S2P or Scap, in contrast to the mammalian system. Flies lacking dS2P are viable and still process dSREBP. dS2P homozygotes were subviable, only emerging at 40% of the expected ratio. This phenotype can be rescued completely by supplementation with fatty acids. dSREBP activity was detected in the fat body of dS2P mutant larvae and to a lesser extent in the oenoctyes. Additionally, SREBP target genes were expressed at higher levels in dS2P homozygotes compared to dSREBP mutants, though less than wild type. dS2P mutants were viable due to alternative cleavage of dSREBP within the juxtamembrane region by the effector caspase, Drice. Flies lacking both dS2P and Drice, or the initiator caspase Dronc, exhibited an early larval lethality that could be rescued by lipid supplementation. Caspase cleavage was dependant upon the aspartic acid at residue 386 in dSREBP. dScap was not essential for larval growth or dSREBP processing in Drosophila. dScap mutants were relatively healthy, emerging at 70% of the expected numbers. dSREBP was actively cleaved in midgut and oenocytes, but significantly reduced in fat body. Levels of dSREBP mRNA and precursor were reduced in larvae lacking dScap, thus demonstrating that Drosophila SREBP is subject to feed-forward ac…
author: Matthews, Krista Ann
language: en
keywords: Sterol Regulatory Element Binding Proteins, Drosophila Melanogaster
date published: 2009-01-14
date modified: 2026-07-27T21:19:01Z
provider: Texas Digital Library
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Texas Digital Library

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property ID: Handle
value: https://hdl.handle.net/2152.5/402