Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism

Bertolio, Rebecca; Napoletano, Francesco; Mano, Miguel; Maurer‐Stroh, Sebastian; Fantuz, Marco; Zannini, Alessandro; Bicciato, Silvio; Sorrentino, Giovanni; Sal, Giannino Del

doi:10.1038/s41467-019-09152-7

Cited by 175 publications

(134 citation statements)

References 60 publications

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“…These studies also suggest that physiological or pathological conditions leading to altered tissue stiffness may affect SREBP activity and lipid metabolism. In line with this hypothesis, altered SREBP1 expression is present in human samples datasets of normal breast tissue with high vs. low mammographic density, and in idiopathic pulmonary fibrosis patients vs. healthy controls [90]. In MS this homoeostatic interplay might be overcome at multiple levels.…”

Section: Chondroitin Sulfate Proteoglycansmentioning

confidence: 72%

“…Treatment of astrocytes with flurosamine reduced the production of CSPGs and, consequently, partial rescued OPC outgrowth on astrocyte ECM (enriched in CSPGs). Very recently, two independent studies have linked the alteration of lipid metabolism to ECM mechanical cues, showing that the physical cell microenvironment modulates the activation of SREBP by affecting translocation of SREBP Cleavage-Activating Protein (SCAP) from the endoplasmic reticulum to the Golgi apparatus and in turn driving lipid synthesis and accumulation [90,91]. These studies also suggest that physiological or pathological conditions leading to altered tissue stiffness may affect SREBP activity and lipid metabolism.…”

Section: Chondroitin Sulfate Proteoglycansmentioning

confidence: 99%

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Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Marangon

Boccazzi

Lecca

et al. 2020

JCM

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Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination.Damage to myelin sheath is present in different severe neurological conditions such as multiple sclerosis (MS), brain ischemia, and amyotrophic lateral sclerosis (ALS). Loss of myelin ultimately results in reduction of nerve conduction velocity and in altered transfer of energy metabolites to neurons which contribute to disease [5,6]. Myelin repair, through the activation, recruitment and differentiation of adult oligodendrocyte precursor cells (OPCs), which become new myelin forming OLs [7], is crucial for limiting axon degeneration and progressive disease disability. During the remyelination process, OPCs undergo profound morphological and functional changes and progressively remodel their membrane composition, increasing the biosynthesis of cholesterol and galactosphingolipids, and reducing the relative amount of phospholipids and proteins [4]. An intricate interaction of environmental signals and cell-intrinsic mechanisms triggered by the immune and inflammatory response to injury is known to limit the regenerative potential of OPCs in MS [8,9]. However, the role of modulators of lipid metabolism in OPC-mediated repair is still not completely elucidated. Of note, recent studies suggest that targeting the lipid pathways in OLs may be a good strategy to promote remyelination [10].Furthermore, in MS, remyelination failure is also strictly correlated to an altered extracellular signaling microenvironment that, among others, affects the organization of OL membranes, which causes defects in myelin at the molecular level [11,12]. Although the ECM is ...

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Section: Chondroitin Sulfate Proteoglycansmentioning

confidence: 72%

Section: Chondroitin Sulfate Proteoglycansmentioning

confidence: 99%

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Marangon

Boccazzi

Lecca

et al. 2020

JCM

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“…In cholesterol deprivation, they translocate from the endoplasmic reticulum to the Golgi apparatus where they are then targeted to the nucleus following cleavage. In the nucleus, they proceed to induce the expression of fatty acid and sterol synthesis (40). SREBP family is composed of SREBP-1 and SREBP-2.…”

Section: Discussionmentioning

confidence: 99%

Regulation of angiotensin converting enzyme 2 (ACE2) in obesity: implications for COVID-19

Heialy

Hachim

Senok

et al. 2020

Preprint

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The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene which is involved in regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow completion of their viral replication cycles. Furthermore, a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs which negatively correlated with the expression of genes that code for sterol response element binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Together our results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.

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“…YAP1 and TAZ transcriptional regulators are a perfect example of such complexity. They serve as a hub for a wide range of stimuli, including biochemical (Hippo, [9]) and metabolic pathways [10,11], mechanical inputs (rigidity, shape, stiffness, cell density and shear stress) [12][13][14][15][16][17][18][19], polarity and other signalling cascades (GPCRs, Akt, JNK) [13,20,21]. YAP1 and TAZ are master regulators of cell proliferation, apoptosis, phenotypic plasticity [22,23] and unsurprisingly they are involved in all the steps of tumorigenesis [24].…”

Section: Introductionmentioning

confidence: 99%

An optogenetic method for interrogating YAP1 and TAZ nuclear-cytoplasmic shuttling

Dowbaj

Jenkins

Heddleston

et al. 2020

Preprint

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The shuttling of transcription factors and transcriptional regulators in and out of the nucleus is central to the regulation of many biological processes. Here we describe a new method for studying the rates of nuclear entry and exit of transcriptional regulators. A photo-responsive AsLOV (Avena sativa Light Oxygen Voltage) domain is used to sequester the transcriptional regulators, YAP1 and TAZ/WWTR1, on the surface of mitochondria. Illumination with blue light is used to release fluorophore-tagged YAP1 and TAZ from mitochondria and their entry into the nucleus can be observed. Cessation of blue light illumination leads to re-sequestration on the surface of mitochondria. This method generates three distinct curves that are then used to fit ordinary differential equations for the rates of nuclear entry and exit. Using this method, we demonstrate that phosphorylation of YAP1 on sites of canonical regulation by LATS1/2 enhances its rate of nuclear export. Moreover, we provide evidences that YAP1 import and export rates, despite high intercellular variability, are correlated within the same cell. Interestingly, the ratio of import and export rates correlated with nuclear-cytoplasmic (NC) distribution of YAP1 and TAZ proteins at steady state.damaging the fluorophore, which limits the researcher's ability to make repeated measurements and typically generates only a single intensity decay curve, which limits the mathematical fitting to derive shuttling rates.During the last decade, several optogenetic systems have been developed to control NC localisation of proteins within a few seconds upon light illumination. Early examples of lightmediated NC shuttling [33,34] led to irreversible nuclear accumulation and they have been surpassed by reversible methods based on light-sensitive proteins. The common idea underlying optogenetic systems is the light-dependent conformational change of photoreceptors fused with the proteins of interest, that can be exploited to manipulate a wide range of cellular processes [35]. Desired protein localization upon light illumination has been achieved with two strategies so far: two-components systems, in which a bait protein is anchored to one compartment and the interaction with the prey protein is light-dependent [36][37][38][39], and one-component systems, in which NES/NLS peptides are caged/exposed upon light illumination [40][41][42][43]. Interestingly, the former strategy has been recently used to develop light-induced control of cellular forces and, as a consequence, of YAP1 localisation [44]. In this work, we exploited an optogenetic tool, namely LOV-TRAP [45,46], for studying NC shuttling based upon light-induced release and sequestration of POI. We present detailed methods for the molecular biology, imaging, and analysis of this tool. Furthermore, the utility of the method is demonstrated by measuring the nuclear import and export rates of mCherry, YAP1, YAP1 mutants, and TAZ. We show that import and export rates, despite the wide intercellular variability, are correlated within th...

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Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism

Cited by 175 publications

References 60 publications

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Regulation of angiotensin converting enzyme 2 (ACE2) in obesity: implications for COVID-19

An optogenetic method for interrogating YAP1 and TAZ nuclear-cytoplasmic shuttling

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