Signaling Networks Converge on TORC1-SREBP Activity to Promote Endoplasmic Reticulum Homeostasis

Sánchez-Álvarez, Miguel; Finger, Fabian; Arias-Garcia, Mar; Bousgouni, Vicky; Pascual-Vargas, Patricia; Bakal, Chris

doi:10.1371/journal.pone.0101164

Cited by 14 publications

(46 citation statements)

References 56 publications

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“…We recently performed genome-scale RNA interference (RNAi) screens in Drosophila cells for genes whose depletion increases, or decreases, activation of the Inositol Requiring Enzyme 1-X-box Binding Protein 1 (IRE1-XBP1) pathway, which is triggered upon induction of ER stress. We found that depletion of genes that promote G1/S transition upregulate the Unfolded Protein Response (UPR), depletion of genes that promote G2/M transition downregulate the UPR ( figure 1 a ; also see [ 17 ]). We validated these observations by real-time polymerase chain reaction (RT-PCR) analysis of endogenous XBP1 splicing, key regulators of cell cycle progression.…”

Section: Resultsmentioning

confidence: 99%

“…We have recently demonstrated that TOR–SREBP regulation of lipid metabolism is required for ER homeostasis [ 17 ]. Thus, in response to growth factors such as insulin, AKT–TOR coordinately upregulates protein translation and lipid anabolism [ 11 , 16 , 17 ]. But it still remains largely unclear as to how activation of AKT–TOR–SREBP signalling is coordinated with cell cycle progression in order to promote membrane homeostasis during growth and division.…”

Section: Introductionmentioning

confidence: 99%

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Cell cycle progression is an essential regulatory component of phospholipid metabolism and membrane homeostasis

et al. 2015

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We show that phospholipid anabolism does not occur uniformly during the metazoan cell cycle. Transition to S-phase is required for optimal mobilization of lipid precursors, synthesis of specific phospholipid species and endoplasmic reticulum (ER) homeostasis. Average changes observed in whole-cell phospholipid composition, and total ER lipid content, upon stimulation of cell growth can be explained by the cell cycle distribution of the population. TORC1 promotes phospholipid anabolism by slowing S/G2 progression. The cell cycle stage-specific nature of lipid biogenesis is dependent on p53. We propose that coupling lipid metabolism to cell cycle progression is a means by which cells have evolved to coordinate proliferation with cell and organelle growth.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell cycle progression is an essential regulatory component of phospholipid metabolism and membrane homeostasis

et al. 2015

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“…Sterol regulatory element‐binding proteins (SREBPs) are inactive precursor proteins anchored to the membrane of the endoplasmic reticulum, which interact with SREBP cleavage‐activating protein (SCAP) to form a complex and mediate cleavage of the transcriptionally active SREBP N‐terminal domain . Two SREBP isoforms, SREBP1 (SREBP1a/SREBP1c) and SREBP2, are found in mammalian cells, and each regulates the expression of genes involved in cholesterol and fatty acid metabolism .…”

Section: Introductionmentioning

confidence: 99%

The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK

Mao

Liu

et al. 2019

The FEBS Journal

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Endoplasmic reticulum (ER) stress and autophagy dysfunction contribute to the establishment and progression of diverse pathologies. Proteolytic activation of the transcription factor nSREBP1 is induced under ER stress; however, little is known about how SREBP1 and its nuclear active form nSREBP1 influence autophagy and unfolded protein response (UPR) activation in osteosarcoma cells. Our research focused on the effect of SREBP1/nSREBP1 upon apoptosis and autophagy during ER stress and the molecular mechanisms involved. Here, we showed that nSREBP1 binds to the promoter of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and then regulates ER stress, cell growth, cell apoptosis, and autophagy through the PERK signaling pathway. nSREBP1 increased PERK gene expression and phosphorylation. nSREBP1 was further demonstrated to activate ER stress response through stimulatory effects on PERK signaling. Overexpression of SREBP1 increased its cleavage and release of nSREBP1; therefore, the effect of SREBP1 is achieved through the enhancement of the expression of nSREBP1. Overexpression of SREBP1/nSREBP1 amplifies PERK-associated cell cycle stagnation with G1 phase arresting, S phase reducing, and G2-M phase delaying. LV-SREBP1/nSREBP1 can also bolster PERK's ER stress-associated proapoptotic effects. LV-SREBP1/nSREBP1 and LV-PERK can activate autophagy in ER stress response, along with the overexpression of SREBP1/nSREBP1 and PERK. This resulted in amplification of PERK-related changes to cell proliferation and ER stress-mediated apoptosis and autophagy, with the biological effect of nSREBP1 relying on PERK, which makes up one of the three branches of the UPR signaling pathway. This study reveals important roles for SREBP1/nSREBP1 in PERK signaling under ER stress. Furthermore, nSREBP1, the nuclear active form of SREBP1, is able to robustly augment the effects of PERK. Description of the link between PERK and SREBP1/nSREBP1 function offers an improved understanding of the ER stress response and insight into the biological function of SREBP1/nSREBP1. Abbreviations ATF4, activating transcription factor-4; CHOP, C/EBP-homologous protein; eIF2a, eukaryotic translation initiation factor-2a; ERAD, endoplasmic reticulum-associated protein degradation; ERS, endoplasmic reticulum stress; INSIG1, insulin-induced gene 1; PERK, protein kinase RNA-like endoplasmic reticulum kinase; SCAP, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBPs, sterol regulatory element-binding proteins; UPR, unfolded protein response.

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“…Therefore, at least some of the signals that control cell proliferation most likely influence ER dynamics. Consistent with this notion, the Target of rapamycin complex 1 (TORC1) signaling pathway has recently been shown to be essential for normal ER morphology and homeostasis in Drosophila cells (Sanchez-Alvarez et al, 2014). However, the developmental control of ER dynamics is still largely unexplored.…”

Section: Introductionmentioning

confidence: 88%

A role for post-transcriptional control of ER dynamics and function in C. elegans germline stem cell maintenance

2016

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Membrane-bound receptors, which are crucial for mediating several key developmental signals, are synthesized on endoplasmic reticulum (ER). The functional integrity of ER must therefore be important for the regulation of at least some developmental programs. However, the developmental control of ER function is not well understood. Here, we identify the C. elegans protein FARL-11, an ortholog of the mammalian STRIPAK complex component STRIP1/2 (FAM40A/B), as an ER protein. In the C. elegans embryo, we find that FARL-11 is essential for the cell cycle-dependent morphological changes of ER and for embryonic viability. In the germline, FARL-11 is required for normal ER morphology and for membrane localization of the GLP-1/Notch receptor involved in germline stem cell (GSC) maintenance. Furthermore, we provide evidence that PUF-8, a key translational regulator in the germline, promotes the translation of farl-11 mRNA. These findings reveal that ER form and function in the C. elegans germline are post-transcriptionally regulated and essential for the niche-GSC signaling mediated by GLP-1.

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Signaling Networks Converge on TORC1-SREBP Activity to Promote Endoplasmic Reticulum Homeostasis

Cited by 14 publications

References 56 publications

Cell cycle progression is an essential regulatory component of phospholipid metabolism and membrane homeostasis

Cell cycle progression is an essential regulatory component of phospholipid metabolism and membrane homeostasis

The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK

A role for post-transcriptional control of ER dynamics and function in C. elegans germline stem cell maintenance

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