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Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism.
Bayraktar EC, La K, Karpman K, Unlu G, Ozerdem C, Ritter DJ, Alwaseem H, Molina H, Hoffmann HH, Millner A, Atilla-Gokcumen GE, Gamazon ER, Rushing AR, Knapik EW, Basu S, Birsoy K
(2020) Nat Metab 2: 487-498
MeSH Terms: Animals, Cell Line, Cell Proliferation, Cholesterol, Gene Expression Regulation, Golgi Apparatus, Humans, Hyperlipidemias, Lipid Metabolism, Membrane Proteins, Proprotein Convertases, Serine Endopeptidases, Sterol Regulatory Element Binding Proteins, Zebrafish
Show Abstract · Added September 9, 2020
Coessentiality mapping has been useful to systematically cluster genes into biological pathways and identify gene functions. Here, using the debiased sparse partial correlation (DSPC) method, we construct a functional coessentiality map for cellular metabolic processes across human cancer cell lines. This analysis reveals 35 modules associated with known metabolic pathways and further assigns metabolic functions to unknown genes. In particular, we identify C12orf49 as an essential regulator of cholesterol and fatty acid metabolism in mammalian cells. Mechanistically, C12orf49 localizes to the Golgi, binds membrane-bound transcription factor peptidase, site 1 (MBTPS1, site 1 protease) and is necessary for the cleavage of its substrates, including sterol regulatory element binding protein (SREBP) transcription factors. This function depends on the evolutionarily conserved uncharacterized domain (DUF2054) and promotes cell proliferation under cholesterol depletion. Notably, c12orf49 depletion in zebrafish blocks dietary lipid clearance in vivo, mimicking the phenotype of mbtps1 mutants. Finally, in an electronic health record (EHR)-linked DNA biobank, C12orf49 is associated with hyperlipidaemia through phenome analysis. Altogether, our findings reveal a conserved role for C12orf49 in cholesterol and lipid homeostasis and provide a platform to identify unknown components of other metabolic pathways.
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14 MeSH Terms
How to thrive in the inflamed gut.
Yoo W, Byndloss MX
(2020) Nat Microbiol 5: 10-11
MeSH Terms: Diet, Enterobacteriaceae, Intestinal Mucosa, Serine
Added March 30, 2020
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4 MeSH Terms
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, Faraway R, Finan C, Valentine D, Fairhurst-Hunter Z, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh K, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Lill CM, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott RA, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Grarup N, Pedersen O, Hansen T, Linneberg A, Jess T, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Lester KH, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Scott R, Schofield P, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Lifelines Cohort authors, Christen T, Mook-Kanamori DO, ICBP Consortium, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Meade T, Christophersen IE, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Roussel R, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Hopewell JC, Seshadri S, METASTROKE Consortium of the ISGC, Dale C, Costa RPE, Ridker PM, Chasman DI, Reiner AP, Ritchie MD, Lange LA, Cornish AJ, Dobbins SE, Hemminki K, Kinnersley B, Sanson M, Labreche K, Simon M, Bondy M, Law P, Speedy H, Allan J, Li N, Went M, Weinhold N, Morgan G, Sonneveld P, Nilsson B, Goldschmidt H, Sud A, Engert A, Hansson M, Hemingway H, Asselbergs FW, Patel RS, Keating BJ, Sattar N, Houlston R, Casas JP, Hingorani AD
(2019) BMC Cardiovasc Disord 19: 240
MeSH Terms: Anticholesteremic Agents, Biomarkers, Brain Ischemia, Cholesterol, LDL, Down-Regulation, Dyslipidemias, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Serine Proteinase Inhibitors, Stroke, Treatment Outcome
Show Abstract · Added March 24, 2020
BACKGROUND - We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.
METHODS - Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.
RESULTS - The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.
CONCLUSIONS - Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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17 MeSH Terms
Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways.
Cheung-Flynn J, Alvis BD, Hocking KM, Guth CM, Luo W, McCallister R, Chadalavada K, Polcz M, Komalavilas P, Brophy CM
(2019) PLoS One 14: e0220893
MeSH Terms: Adenosine Triphosphate, Animals, Aorta, Cell Membrane, Endothelial Cells, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Rats, Receptors, Purinergic P2X7, Saline Solution, Saphenous Vein, Signal Transduction, Swine, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 3, 2020
Resuscitation with 0.9% Normal Saline (NS), a non-buffered acidic solution, leads to increased morbidity and mortality in the critically ill. The goal of this study was to determine the molecular mechanisms of endothelial injury after exposure to NS. The hypothesis of this investigation is that exposure of endothelium to NS would lead to loss of cell membrane integrity, resulting in release of ATP, activation of the purinergic receptor (P2X7R), and subsequent activation of stress activated signaling pathways and inflammation. Human saphenous vein endothelial cells (HSVEC) incubated in NS, but not buffered electrolyte solution (Plasma-Lyte, PL), exhibited abnormal morphology and increased release of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and decreased transendothelial resistance (TEER), suggesting loss of membrane integrity. Incubation of intact rat aorta (RA) or human saphenous vein in NS but not PL led to impaired endothelial-dependent relaxation which was ameliorated by apyrase (hydrolyzes ATP) or SB203580 (p38 MAPK inhibitor). Exposure of HSVEC to NS but not PL led to activation of p38 MAPK and its downstream substrate, MAPKAP kinase 2 (MK2). Treatment of HSVEC with exogenous ATP led to interleukin 1β (IL-1β) release and increased vascular cell adhesion molecule (VCAM) expression. Treatment of RA with IL-1β led to impaired endothelial relaxation. IL-1β treatment of HSVEC led to increases in p38 MAPK and MK2 phosphorylation, and increased levels of arginase II. Incubation of porcine saphenous vein (PSV) in PL with pH adjusted to 6.0 or less also led to impaired endothelial function, suggesting that the acidic nature of NS is what contributes to endothelial dysfunction. Volume overload resuscitation in a porcine model after hemorrhage with NS, but not PL, led to acidosis and impaired endothelial function. These data suggest that endothelial dysfunction caused by exposure to acidic, non-buffered NS is associated with loss of membrane integrity, release of ATP, and is modulated by P2X7R-mediated inflammatory responses.
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17 MeSH Terms
Arrestin-3 interaction with maternal embryonic leucine-zipper kinase.
Perry NA, Fialkowski KP, Kaoud TS, Kaya AI, Chen AL, Taliaferro JM, Gurevich VV, Dalby KN, Iverson TM
(2019) Cell Signal 63: 109366
MeSH Terms: Arrestins, HEK293 Cells, Humans, Protein Binding, Protein-Serine-Threonine Kinases, S Phase
Show Abstract · Added March 18, 2020
Maternal embryonic leucine-zipper kinase (MELK) overexpression impacts survival and proliferation of multiple cancer types, most notably glioblastomas and breast cancer. This makes MELK an attractive molecular target for cancer therapy. Yet the molecular mechanisms underlying the involvement of MELK in tumorigenic processes are unknown. MELK participates in numerous protein-protein interactions that affect cell cycle, proliferation, apoptosis, and embryonic development. Here we used both in vitro and in-cell assays to identify a direct interaction between MELK and arrestin-3. A part of this interaction involves the MELK kinase domain, and we further show that the interaction between the MELK kinase domain and arrestin-3 decreases the number of cells in S-phase, as compared to cells expressing the MELK kinase domain alone. Thus, we describe a new mechanism of regulation of MELK function, which may contribute to the control of cell fate.
Copyright © 2019 Elsevier Inc. All rights reserved.
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6 MeSH Terms
IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.
Chopra S, Giovanelli P, Alvarado-Vazquez PA, Alonso S, Song M, Sandoval TA, Chae CS, Tan C, Fonseca MM, Gutierrez S, Jimenez L, Subbaramaiah K, Iwawaki T, Kingsley PJ, Marnett LJ, Kossenkov AV, Crespo MS, Dannenberg AJ, Glimcher LH, Romero-Sandoval EA, Cubillos-Ruiz JR
(2019) Science 365:
MeSH Terms: Animals, Cells, Cultured, Cyclooxygenase 2, Dinoprostone, Endoribonucleases, Humans, Leukocytes, Mice, Mice, Inbred C57BL, Myeloid Cells, Pain, Postoperative, Promoter Regions, Genetic, Prostaglandin-E Synthases, Protein-Serine-Threonine Kinases, Signal Transduction, Unfolded Protein Response, Visceral Pain, X-Box Binding Protein 1
Show Abstract · Added March 12, 2020
Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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18 MeSH Terms
Control of antiviral innate immune response by protein geranylgeranylation.
Yang S, Harding AT, Sweeney C, Miao D, Swan G, Zhou C, Jiang Z, Fitzgerald KA, Hammer G, Bergo MO, Kroh HK, Lacy DB, Sun C, Glogauer M, Que LG, Heaton NS, Wang D
(2019) Sci Adv 5: eaav7999
MeSH Terms: Adaptor Proteins, Signal Transducing, Alkyl and Aryl Transferases, Animals, Endoplasmic Reticulum, Female, Humans, Immunity, Innate, Macrophages, Alveolar, Male, Mice, Knockout, Neuropeptides, Orthomyxoviridae Infections, Protein Prenylation, Receptor-Interacting Protein Serine-Threonine Kinases, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, rac GTP-Binding Proteins, rac1 GTP-Binding Protein
Show Abstract · Added March 24, 2020
The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIP to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.
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18 MeSH Terms
Energy metabolism couples hepatocyte integrin-linked kinase to liver glucoregulation and postabsorptive responses of mice in an age-dependent manner.
Trefts E, Hughey CC, Lantier L, Lark DS, Boyd KL, Pozzi A, Zent R, Wasserman DH
(2019) Am J Physiol Endocrinol Metab 316: E1118-E1135
MeSH Terms: Age Factors, Animals, Blood Glucose, Cell Differentiation, Cell Respiration, Energy Metabolism, Gene Knockout Techniques, Glucose, Glucose Tolerance Test, Hepatocytes, Homeostasis, Inflammation, Insulin, Insulin Resistance, Liver, Liver Cirrhosis, Mice, Obesity, Protein-Serine-Threonine Kinases
Show Abstract · Added March 26, 2019
Integrin-linked kinase (ILK) is a critical intracellular signaling node for integrin receptors. Its role in liver development is complex, as ILK deletion at E10.5 (before hepatocyte differentiation) results in biochemical and morphological differences that resolve as mice age. Nevertheless, mice with ILK depleted specifically in hepatocytes are protected from the hepatic insulin resistance during obesity. Despite the potential importance of hepatocyte ILK to metabolic health, it is unknown how ILK controls hepatic metabolism or glucoregulation. The present study tested the role of ILK in hepatic metabolism and glucoregulation by deleting it specifically in hepatocytes, using a cre-lox system that begins expression at E15.5 (after initiation of hepatocyte differentiation). These mice develop the most severe morphological and glucoregulatory abnormalities at 6 wk, but these gradually resolve with age. After identifying when the deletion of ILK caused a severe metabolic phenotype, in depth studies were performed at this time point to define the metabolic programs that coordinate control of glucoregulation that are regulated by ILK. We show that 6-wk-old ILK-deficient mice have higher glucose tolerance and decreased net glycogen synthesis. Additionally, ILK was shown to be necessary for transcription of mitochondrial-related genes, oxidative metabolism, and maintenance of cellular energy status. Thus, ILK is required for maintaining hepatic transcriptional and metabolic programs that sustain oxidative metabolism, which are required for hepatic maintenance of glucose homeostasis.
1 Communities
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19 MeSH Terms
Treating Nonalcoholic Fatty Liver Disease From the Outside In?
Flynn CR
(2019) Cell Mol Gastroenterol Hepatol 7: 682-683
MeSH Terms: Animals, Hepatocytes, Intracellular Signaling Peptides and Proteins, Mice, Non-alcoholic Fatty Liver Disease, Oligonucleotides, Antisense, Protein-Serine-Threonine Kinases
Added April 15, 2019
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7 MeSH Terms
Cyclin G1 and TASCC regulate kidney epithelial cell G-M arrest and fibrotic maladaptive repair.
Canaud G, Brooks CR, Kishi S, Taguchi K, Nishimura K, Magassa S, Scott A, Hsiao LL, Ichimura T, Terzi F, Yang L, Bonventre JV
(2019) Sci Transl Med 11:
MeSH Terms: Animals, Autophagy, Cell Compartmentation, Cell Cycle Checkpoints, Cell Dedifferentiation, Cyclin G1, Disease Models, Animal, Disease Progression, Epithelial Cells, Fibrosis, Humans, Kidney, Kidney Tubules, Proximal, LLC-PK1 Cells, Male, Mice, Renal Insufficiency, Chronic, Swine, TOR Serine-Threonine Kinases, Wound Healing
Show Abstract · Added March 14, 2019
Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G-M arrest in PTCs and up-regulated TASCC formation. PTC TASCC formation was also present in humans with CKD. Prevention of TASCC formation in cultured PTCs blocked secretion of profibrotic factors. PTC-specific knockout of a key TASCC component reduced the rate of kidney fibrosis progression in mice with CKD. CG1 induction and TASCC formation also occur in liver fibrosis. Deletion of CG1 reduced G-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G-M arrest is induced in kidney injury and how G-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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20 MeSH Terms