Abstract
The function and capacity of the endoplasmic reticulum (ER) is determined by multiple processes ranging from the local regulation of peptide translation, translocation, and folding, to global changes in lipid composition. ER homeostasis thus requires complex interactions amongst numerous cellular components. However, describing the networks that maintain ER function during changes in cell behavior and environmental fluctuations has, to date, proven difficult. Here we perform a systems-level analysis of ER homeostasis, and find that although signaling networks that regulate ER function have a largely modular architecture, the TORC1-SREBP signaling axis is a central node that integrates signals emanating from different sub-networks. TORC1-SREBP promotes ER homeostasis by regulating phospholipid biosynthesis and driving changes in ER morphology. In particular, our network model shows TORC1-SREBP serves to integrate signals promoting growth and G1-S progression in order to maintain ER function during cell proliferation.
Highlights
The endoplasmic reticulum (ER) harbors the cellular machinery responsible for protein folding, maturation, trafficking and secretion; calcium homeostasis; and the metabolism of complex lipids
We identified five major classes of genes whose depletion significantly up-regulates ER stress in Sterol Regulatory Element Binding Protein (SREBP) deficient cells: i) genes involved in the starvation response, such as foxo; ii) genes involved in general stress responses and survival; iii) genes regulating autophagy; iv) genes involved in calcium homeostasis; and v) genes involved in chromatin remodeling
Splicing of endogenous XBP1 mRNA was assessed by RT-PCR
Summary
The endoplasmic reticulum (ER) harbors the cellular machinery responsible for protein folding, maturation, trafficking and secretion; calcium homeostasis; and the metabolism of complex lipids. ER homeostasis must be maintained during cellular events that place a functional demand on the ER, such as cell growth and proliferation, differentiation, or activation of secretion, as well as during fluctuations in environmental conditions. An ancient signaling system, termed the Unfolded Protein Response (UPR), has evolved to continuously monitor the luminal ER environment, and engage a cellular program that promotes ER homeostasis [2,3,4]. The UPR comprises at least three sub-branches in higher eukaryotes, each dependent on a specific molecular transducer: Inositol Requiring Enzyme 1 (IRE1), PKR-like Endoplasmic Reticulum associated Kinase (PERK) and Activating Transcription Factor 6 (ATF6). Upon engagement of ER stress, IRE1 catalyzes the splicing of a short fragment of the mRNA encoded by the X-
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