The ins and outs of endoplasmic reticulum‐controlled lipid biosynthesis

Jacquemyn, Julie; Cascalho, Ana

doi:10.15252/embr.201643426

Cited by 221 publications

(203 citation statements)

References 141 publications

(185 reference statements)

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“…The synthesis of most major cellular lipids, including phospholipids, sterols, and sphingolipids, is known to start in the ER (Jacquemyn et al, 2017; Ron and Hampton, 2004). A series of observations indicate that the UPR components IRE1 and PERK can be activated by a lipotoxic stress that is caused by adding free fatty acids; in those instances activation has been proposed to occur by the fatty acids increasing membrane fluidity, with the increased fluidity being the signal for UPR activation (Volmer et al, 2013; Halbleib et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

et al. 2018

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The unfolded protein response (UPR) is induced by proteotoxic stress of the endoplasmic reticulum (ER). Here we report that ATF6, a major mammalian UPR sensor, is also activated by specific sphingolipids, dihydrosphingosine (DHS) and dihydroceramide (DHC). Single mutations in a previously undefined transmembrane domain motif that we identify in ATF6 incapacitate DHS/DHC activation while still allowing proteotoxic stress activation via the luminal domain. ATF6 thus possesses two activation mechanisms: DHS/DHC activation and proteotoxic stress activation. Reporters constructed to monitor each mechanism show that phenobarbital-induced ER membrane expansion depends on transmembrane domain-induced ATF6. DHS/DHC addition preferentially induces transcription of ATF6 target lipid biosynthetic and metabolic genes over target ER chaperone genes. Importantly, ATF6 containing a luminal achromatopsia eye disease mutation, unresponsive to proteotoxic stress, can be activated by fenretinide, a drug that upregulates DHC, suggesting a potential therapy for this and other ATF6-related diseases including heart disease and stroke.

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Section: Introductionmentioning

confidence: 99%

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

et al. 2018

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“…8,[43][44][45] In principle, protein phosphorylation (or other modifications) could play a role in acute regulation of GPL compositions since those processes can take place rapidly and can influence protein activity. [46][47][48][49] However, this mechanism requires the existence of proteins that accurately "sense" the change in the GPL class composition of the membrane. As far as we are aware, no such proteins have been identified in mammalian cells so far.…”

Section: Other Modes Of Regulationmentioning

confidence: 99%

“…Those “coarse” mechanisms rather come into play when a change in GPL composition is required as, for example, during mitosis, cell differentiation or by altered cellular environment . In principle, protein phosphorylation (or other modifications) could play a role in acute regulation of GPL compositions since those processes can take place rapidly and can influence protein activity . However, this mechanism requires the existence of proteins that accurately “sense” the change in the GPL class composition of the membrane.…”

Section: Introductionmentioning

confidence: 99%

Hypothesis: Chemical activity regulates and coordinates the processes maintaining glycerophospholipid homeostasis in mammalian cells

2020

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Mammalian cells maintain the complex glycerophospholipid (GPL) class compositions of their various membranes within close limits because this is essential to their well‐being or viability. Surprisingly, however, it is still not understood how those compositions are maintained except that GPL synthesis and degradation are closely coordinated. Here, we hypothesize that abrupt changes in the chemical activity of the individual GPL classes coordinate synthesis and degradation as well other the homeostatic processes. We have previously proposed that only a limited number of “allowed” or “optimal” GPL class compositions exist in cellular membranes because those compositions are energetically more favorable than others, that is, they represent local free energy minima (Somerharju et al 2009, Biochim. Biophys. Acta 1788, 12‐23). This model, however, could not satisfactorily explain how the “optimal” compositions are sensed by the key homeostatic enzymes, that is, rate‐limiting synthetizing enzymes and homeostatic phospholipases. We now hypothesize that when the mole fraction of a GPL class exceeds an optimal value, its chemical activity abruptly increases which (a) increases its propensity to efflux from the membrane thus making it susceptible for hydrolysis by homeostatic phospholipases; (b) increases its potency to inhibit its own biosynthesis via a feedback mechanism; (c) enhances its conversion to another glycerophospholipid class via a novel process termed “head group remodeling” or (d) enhances its translocation to other subcellular membranes. In summary, abrupt change in the chemical activity of the individual GPL classes is proposed to regulate and coordinate those four processes maintaining GPL class homeostasis in mammalian cells.

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“…The small diameter of the tubules and their relatively rapid dynamics mean that detailed quantitative analysis has only become possible with recent developments in microscopy, such as super-resolution fluorescence microscopy (3). The ER is responsible for the biosynthesis of many proteins and lipids, as well as calcium ion storage and regulation (4)(5)(6). Almost all other subcellular organelles interact with the ER at membrane contact sites (MCS) (7), including mitochondria (8)(9)(10)(11), endosomes (12)(13)(14)(15), the Golgi apparatus (16) and the plasma membrane (17).…”

Section: Introductionmentioning

confidence: 99%

Network Organisation and the Dynamics of Tubules in the Endoplasmic Reticulum

Perkins

Ducluzaux

Woodman

et al. 2020

Preprint

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The endoplasmic reticulum (ER) is a eukaryotic subcellular organelle composed of tubules and sheetlike areas of membrane connected at junctions. The tubule network is highly dynamic and undergoes rapid and continual rearrangement. There are currently few tools to evaluate network organisation and dynamics. We quantified ER network organisation in Vero and MRC5 cells, and developed a classification system for ER dynamics in live cells. The persistence length, tubule length, junction coordination number and angles of the network were quantified. Hallmarks of imbalances in ER tension, indications of interactions with microtubules and other subcellular organelles, and active reorganisation and dynamics were observed. Live cell ER tubule dynamics were classified using a Gaussian mixture model, defining tubule motion as active or thermal and conformational phase space analysis allowed this classification to be refined by tubule curvature states. STATEMENT OF SIGNIFICANCEThe endoplasmic reticulum (ER), a subcellular organelle, is an underexplored real-world example of active matter. Many processes essential to cell survival are performed by the ER, the efficacy of which may depend on its organisation and dynamics. Abnormal ER morphology is linked to diseases such as hereditary spastic paraplegias and it is possible that the dynamics are also implicated. Therefore, analysing the ER network in normal cells is important for the understanding of diseaserelated alterations. In this work, we outline the first thorough quantification methods for determining ER organisation and dynamics, deducing that tubule motion has a binary classification as active or thermal. Active reorganisation and dynamics along with indications of tension imbalances and membrane contact sites were observed.

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The ins and outs of endoplasmic reticulum‐controlled lipid biosynthesis

Cited by 221 publications

References 141 publications

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

Hypothesis: Chemical activity regulates and coordinates the processes maintaining glycerophospholipid homeostasis in mammalian cells

Network Organisation and the Dynamics of Tubules in the Endoplasmic Reticulum

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