BAG3 Plays a Central Role in Proteostasis in the Heart

Total Page:16

File Type:pdf, Size:1020Kb

BAG3 Plays a Central Role in Proteostasis in the Heart COMMENTARY The Journal of Clinical Investigation BAG3 plays a central role in proteostasis in the heart Wataru Mizushima and Junichi Sadoshima Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey, USA. These mechanisms include aggresome formation through retrograde transport of Proteinopathies are characterized by the accumulation of misfolded misfolded proteins, which depends on the proteins, which ultimately interfere with normal cell function. While interaction of BAG3 with dynein motors neurological diseases, such as Huntington disease and Alzheimer disease, and the microtubule organization center are well-characterized proteinopathies, cardiac diseases have recently been (9), and stimulation of autophagy, which associated with alterations in proteostasis. In this issue of the JCI, Fang and depends on BAG3 interaction with HSPB8. colleagues demonstrate that mice with cardiac-specific deficiency of the Both retrograde transport and autophagy co-chaperone protein BCL2-associated athanogene 3 (BAG3) develop dilated facilitate the sequestration and removal of cardiomyopathy that is associated with a destabilization of small HSPs as irreversibly misfolded proteins. BAG3 is the result of a disrupted interaction between BAG3 and HSP70. Together, also involved in chaperone-assisted selec- the results of this study suggest that strategies to upregulate BAG3 during tive autophagy (CASA). CASA is a cargo- cardiac dysfunction may be beneficial. selective form of autophagy that is mediated through the HSC70-BAG3-HSPB8 complex and allows ubiquitination of selected pro- teins recognized by HSC70 via the CHIP Protein aggregates and disease suggest that proteotoxicity is also involved ubiquitin ligase and sequestration by auto- Protein homeostasis (proteostasis) is essen- in the pathogenesis of many heart diseases, phagosomes through the LC3 adapter p62/ tial for maintaining normal cell function (1, including cardiomyopathy and heart failure. SQSTM in the presence of synaptopodin 2 2). Proper protein activity is achieved through Cells possess several protein quality control or DNAJB6 (10). In muscles, BAG3 is partic- rigorous coordination of synthesis, folding, (PQC) mechanisms, comprising chaperones ularly important for maintaining the struc- and posttranslational modification, all of and protein degradation systems, including ture and integrity of sarcomeres through which are prone to malfunction in response the ubiquitin-proteasome system (UPS) and its interaction with HSC70 and an actin- to stress. For example, protein folding in the autophagy-lysosome system, that help min- capping sarcomeric protein (actin-capping endoplasmic reticulum (ER) is easily disrupt- imize proteotoxicity. Chaperones function protein β1) (11). In mice, a homozygous null ed in the presence of ER stress and oxidative as the first line of defense by either refolding mutation of Bag3 causes a fulminant form stress. Disruption of proteostasis induces misfolded proteins or by promoting the deg- of dilated cardiomyopathy (DCM) (12). In the accumulation of misfolded proteins, radation of misfolded or damaged proteins addition, a genome-wide association study which then interfere with the normal func- that are not suitable for refolding via the UPS (GWAS) identified several mutations in tion of cells through improper degradation, or autophagy. Accumulation of misfolded BAG3, including an E455K mutation in the gain and/or loss of function, and aggregate proteins occurs through dysregulation of evolutionarily conserved BAG domain, that formation. The adverse effects caused by PQC mechanisms, and the consequent pro- underlie a familial form of DCM (13). How- altered proteostasis are collectively termed teotoxicity develops through many different ever, the molecular mechanism through proteotoxicity, and pathological conditions mechanisms. In vivo animal models have which the loss of BAG3 function in cardio- resulting from proteotoxicity are collectively proven quite useful in elucidating the molec- myocytes leads to the development of DCM termed proteinopathies (3, 4). Proteostasis is ular mechanisms of proteinopathy (6). remains to be elucidated. particularly important for postmitotic cells, BCL2-associated athanogene 3 (BAG3) such as neurons and adult cardiomyocytes, is a co-chaperone protein that regulates the Loss of BAG3 function alters that have negligible regenerative poten- ATPase activity of the HSP70 family and is PQC in murine DCM tial, because in these mature cells, proteo- predominantly expressed in striated mus- In this issue, Fang and colleagues used toxicity is not readily diluted through cell cles (7, 8). BAG3 has been studied exten- mice with cardiac-specific deletion of division. The concept of proteinopathy was sively during the past decade, because, Bag3 (herein referred to as cKO mice) initially used to explain the pathogenesis together with small HSPB8, it directs the and mice with cardiac-specific expres- of neurodegenerative diseases, including HSP70 chaperone complex to other pro- sion of BAG3E455K (herein referred to as Huntington disease and Alzheimer disease teins involved in major cellular functions, cMUT mice) and demonstrated that loss (5); however, several lines of evidence now thereby mediating key PQC mechanisms. of function of BAG3 induces the develop- ment of DCM by attenuating PQC over Related Article: p. 3189 a specific subset of proteins involved in metabolic and contractile functions in Conflict of interest: The authors have declared that no conflict of interest exists. cardiomyocytes (14). Downregulation of Reference information: J Clin Invest. 2017;127(8):2900–2903. https://doi.org/10.1172/JCI95839. BAG3 or expression of BAG3E455K disrupt- 2900 jci.org Volume 127 Number 8 August 2017 The Journal of Clinical Investigation COMMENTARY Figure 1. Putative functions of BAG3 in the heart and the underlying mechanisms of cardiomyopathy caused by loss of BAG3 function. BAG3 plays a critical role in the PQC system in the heart. WT BAG3 forms multi-chaperone complexes with HSP70/HSC70 and sHSPs via its IPV motif and BAG3 domain. The BAG3-HSPB8-HSC70 complex binds to misfolded proteins and either promotes refolding or degradation of these misfolded proteins. Degradation is mediated primarily through general autophagy. The BAG3-HSPB8-HSC70 complex also maintains the structure and integrity of sarcomeres via CASA, a substrate-specific form of autophagy. In addition, BAG3 binds to dynein via the proline-rich motif (PXXP) and segregates misfolded proteins into aggresomes located in the perinuclear space through retrograde transport. The BAG3E455K mutation, which is located in the middle of the BAG domain, attenuates the interaction between BAG3 and HSP70/HSC70, leading to destabilization of sHSPs, including HSPB8. This disturbance of the chaperone complexes induces dysregulation of the refolding and degradation processes (autophagy and CASA), resulting in accumulation of BAG3 complex substrate proteins involved in metabolism and cardiac contraction in the detergent-insoluble fraction. Interestingly, aggresomes are not obvious in the BAG3 loss-of-function mouse model, possibly because of the defect in retrograde transport. Despite the absence of large protein aggregates, BAG3 loss-of-function mice develop DCM. ed the interaction between BAG3 and dysfunction. This proposed contribution thy, overexpression of BAG3P209L induces HSP70 and consequently downregulated of small aggregates to cardiac dysfunction the formation of myofibrillar aggregates several small HSPs (sHSPs), including in cKO and cMUT mice is similar to a study that sequester functional WT BAG3, HSPB5, HSPB6, and HSPB8, through pro- that demonstrated that the presence of sol- thereby acting in a toxic gain-of-func- tein destabilization. As a result, both pro- uble preamyloid oligomers (PAOs) is suffi- tion manner (17). More extensive ultra- tein refolding and degradation of selected cient to induce cardiomyocyte dysfunction structural and biochemical analyses of HSP70-BAG3-HSPB8 complex–interact- in desmin cardiomyopathy mouse models the proteotoxicity associated with the ing proteins, many of which are involved (16). It is possible that aggresome forma- different BAG3 mutants and of the pres- in metabolism and cardiac contraction, tion through BAG3-mediated retrograde ence of preamyloid oligomers would be were suppressed, resulting in accumula- transport may even be an adaptive process helpful to address this issue. Alternative- tion of these proteins in the detergent-in- to protect cardiomyocytes from the toxici- ly, the depletion of some proteins in the soluble fraction (Figure 1). ty caused by small protein aggregates. soluble fraction may be more important Interestingly, large protein aggregates and directly cause the functional defi- were not observed in cKO or cMUT mice, Remaining questions and cit in the BAG3 loss-of-function mouse despite a drastic increase in the amount future directions models. Fang et al. show that a limited of proteins in the detergent-insoluble Although the study by Fang et al. clearly number of proteins involved in muscle fraction. As BAG3 and HSPB8 are critical suggests that proper coordination of the contraction, actin filament capping, pro- regulators of dynein-mediated retrograde actions of HSP70, BAG3, and HSPB8 is tein folding, mitochondrial organization, transport (15), aggresome formation may essential for the maintenance of PQC and cell junction assembly
Recommended publications
  • Atlas Antibodies in Breast Cancer Research Table of Contents
    ATLAS ANTIBODIES IN BREAST CANCER RESEARCH TABLE OF CONTENTS The Human Protein Atlas, Triple A Polyclonals and PrecisA Monoclonals (4-5) Clinical markers (6) Antibodies used in breast cancer research (7-13) Antibodies against MammaPrint and other gene expression test proteins (14-16) Antibodies identified in the Human Protein Atlas (17-14) Finding cancer biomarkers, as exemplified by RBM3, granulin and anillin (19-22) Co-Development program (23) Contact (24) Page 2 (24) Page 3 (24) The Human Protein Atlas: a map of the Human Proteome The Human Protein Atlas (HPA) is a The Human Protein Atlas consortium cell types. All the IHC images for Swedish-based program initiated in is mainly funded by the Knut and Alice the normal tissue have undergone 2003 with the aim to map all the human Wallenberg Foundation. pathology-based annotation of proteins in cells, tissues and organs expression levels. using integration of various omics The Human Protein Atlas consists of technologies, including antibody- six separate parts, each focusing on References based imaging, mass spectrometry- a particular aspect of the genome- 1. Sjöstedt E, et al. (2020) An atlas of the based proteomics, transcriptomics wide analysis of the human proteins: protein-coding genes in the human, pig, and and systems biology. mouse brain. Science 367(6482) 2. Thul PJ, et al. (2017) A subcellular map of • The Tissue Atlas shows the the human proteome. Science. 356(6340): All the data in the knowledge resource distribution of proteins across all eaal3321 is open access to allow scientists both major tissues and organs in the 3.
    [Show full text]
  • HCC and Cancer Mutated Genes Summarized in the Literature Gene Symbol Gene Name References*
    HCC and cancer mutated genes summarized in the literature Gene symbol Gene name References* A2M Alpha-2-macroglobulin (4) ABL1 c-abl oncogene 1, receptor tyrosine kinase (4,5,22) ACBD7 Acyl-Coenzyme A binding domain containing 7 (23) ACTL6A Actin-like 6A (4,5) ACTL6B Actin-like 6B (4) ACVR1B Activin A receptor, type IB (21,22) ACVR2A Activin A receptor, type IIA (4,21) ADAM10 ADAM metallopeptidase domain 10 (5) ADAMTS9 ADAM metallopeptidase with thrombospondin type 1 motif, 9 (4) ADCY2 Adenylate cyclase 2 (brain) (26) AJUBA Ajuba LIM protein (21) AKAP9 A kinase (PRKA) anchor protein (yotiao) 9 (4) Akt AKT serine/threonine kinase (28) AKT1 v-akt murine thymoma viral oncogene homolog 1 (5,21,22) AKT2 v-akt murine thymoma viral oncogene homolog 2 (4) ALB Albumin (4) ALK Anaplastic lymphoma receptor tyrosine kinase (22) AMPH Amphiphysin (24) ANK3 Ankyrin 3, node of Ranvier (ankyrin G) (4) ANKRD12 Ankyrin repeat domain 12 (4) ANO1 Anoctamin 1, calcium activated chloride channel (4) APC Adenomatous polyposis coli (4,5,21,22,25,28) APOB Apolipoprotein B [including Ag(x) antigen] (4) AR Androgen receptor (5,21-23) ARAP1 ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1 (4) ARHGAP35 Rho GTPase activating protein 35 (21) ARID1A AT rich interactive domain 1A (SWI-like) (4,5,21,22,24,25,27,28) ARID1B AT rich interactive domain 1B (SWI1-like) (4,5,22) ARID2 AT rich interactive domain 2 (ARID, RFX-like) (4,5,22,24,25,27,28) ARID4A AT rich interactive domain 4A (RBP1-like) (28) ARID5B AT rich interactive domain 5B (MRF1-like) (21) ASPM Asp (abnormal
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Ikkγ Protein Is a Target of BAG3 Regulatory Activity in Human Tumor Growth
    IKKγ protein is a target of BAG3 regulatory activity in human tumor growth Massimo Ammirantea,b,1, Alessandra Rosatib,c,1, Claudio Arrac,d, Anna Basileb,c, Antonia Falcob,c, Michela Festab,c, Maria Pascaleb,c, Morena d’Aveniab,c, Liberato Marzullob,c, Maria Antonietta Belisariob, Margot De Marcob,c, Antonio Barbierid, Aldo Giudiced, Gennaro Chiappettae, Emilia Vuttarielloe, Mario Monacoe, Patrizia Bonellid, Gaetano Salvatoref, Maria Di Benedettof, Satish L. Deshmaneg, Kamel Khalilig, Maria Caterina Turcob,c,2, and Arturo Leoneb aLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0723; bDepartment of Pharmaceutical Sciences (DiFarma), University of Salerno, 84084 Fisciano, Italy; cBioUniverSA S.R.L., 84084 Fisciano, Italy; dAnimal Facility and eFunctional Genomic Unit National Cancer Institute, “Tumor Institute Fond. Pascale,” 80131 Naples, Italy; fPathological Anatomy, Federico II University, 80131 Naples, Italy; and gCenter For Neurovirology, Department of Neuroscience, Temple University, Philadelphia PA 19122 Edited* by Michael Karin, School of Medicine, University of California, La Jolla, CA, and approved March 17, 2010 (received for review July 10, 2009) BAG3, a member of the BAG family of heat shock protein (HSP) 70 leukemia results in a dramatic increase of basal as well as drug- cochaperones, is expressed in response to stressful stimuli in a number induced apoptosis (17, 18). Furthermore, BAG3 is overexpressed in of normal cell types and constitutively in a variety of tumors, including thyroid carcinomas, where higher levels of expression are reached in pancreas carcinomas, lymphocytic and myeloblastic leukemias, and anaplastic tumors compared with well-differentiated forms.
    [Show full text]
  • The Apoptosis Database
    Cell Death and Differentiation (2003) 10, 621–633 & 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00 www.nature.com/cdd Review The apoptosis database KS Doctor1, JC Reed1, A Godzik1 and PE Bourne*,1,2 Introduction 1 The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, The set of known proteins that directly regulate apoptosis has USA 2 San Diego Supercomputer Center, University of California San Diego, 9500 grown rapidly over the last 15 years. This growth will continue Gilman Drive, La Jolla, CA 92093-0505, USA until all the proteins directly involved in the cell death signaling * Corresponding author: PE Bourne, Tel: 858-534-8301; Fax: 858-822-0873, process are known. This assortment of proteins with wide E-mail: [email protected] ranging biochemical functions is linked together conceptually in the minds of apoptosis researchers. Assembling an up-to- Received 10.9.02; revised 3.12.02; accepted 10.12.02 date view of this conceptual collection of proteins within the Edited by Dr Green context of apoptosis requires a considerable effort, or more specifically, complete immersion into the field. One principal Abstract goal of an apoptosis review article is to assemble such a collection of protein annotations as an educational and The apoptosis database is a public resource for researchers research resource. The apoptosis database described here and students interested in the molecular biology of apoptosis. is designed to fulfil the same goal, but to immediately allow the The resource provides functional annotation, literature user to dig deeper using local and remote information and to references, diagrams/images, and alternative nomenclatures always remain current with respect to the proteins known to be on a set of proteins having ‘apoptotic domains’.
    [Show full text]
  • Bag6 Complex Contains a Minimal Tail-Anchor–Targeting Module and a Mock BAG Domain
    Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain Jee-Young Mocka, Justin William Chartrona,Ma’ayan Zaslavera,YueXub,YihongYeb, and William Melvon Clemons Jr.a,1 aDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; and bLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved December 1, 2014 (received for review February 12, 2014) BCL2-associated athanogene cochaperone 6 (Bag6) plays a central analogous yeast complex contains two proteins, Get4 and Get5/ role in cellular homeostasis in a diverse array of processes and is Mdy2, which are homologs of the mammalian proteins TRC35 part of the heterotrimeric Bag6 complex, which also includes and Ubl4A, respectively. In yeast, these two proteins form ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition a heterotetramer that regulates the handoff of the TA protein complex 35 (TRC35). This complex recently has been shown to be from the cochaperone small, glutamine-rich, tetratricopeptide important in the TRC pathway, the mislocalized protein degrada- repeat protein 2 (Sgt2) [small glutamine-rich tetratricopeptide tion pathway, and the endoplasmic reticulum-associated degrada- repeat-containing protein (SGTA) in mammals] to the delivery tion pathway. Here we define the architecture of the Bag6 factor Get3 (TRC40 in mammals) (19–22). It is expected that the complex, demonstrating that both TRC35 and Ubl4A have distinct mammalian homologs, along with Bag6, play a similar role (23– C-terminal binding sites on Bag6 defining a minimal Bag6 complex.
    [Show full text]
  • The HSP70 Chaperone Machinery: J Proteins As Drivers of Functional Specificity
    REVIEWS The HSP70 chaperone machinery: J proteins as drivers of functional specificity Harm H. Kampinga* and Elizabeth A. Craig‡ Abstract | Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that function in a myriad of biological processes, modulating polypeptide folding, degradation and translocation across membranes, and protein–protein interactions. This multitude of roles is not easily reconciled with the universality of the activity of HSP70s in ATP-dependent client protein-binding and release cycles. Much of the functional diversity of the HSP70s is driven by a diverse class of cofactors: J proteins. Often, multiple J proteins function with a single HSP70. Some target HSP70 activity to clients at precise locations in cells and others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate. In their native cellular environment, polypeptides are participates in such diverse cellular functions. Their constantly at risk of attaining conformations that pre- functional diversity is remarkable considering that vent them from functioning properly and/or cause them within and across species, HSP70s have high sequence to aggregate into large, potentially cytotoxic complexes. identity. They share a single biochemical activity: an Molecular chaperones guide the conformation of proteins ATP-dependent client-binding and release cycle com- throughout their lifetime, preventing their aggregation bined with client protein recognition, which is typi- by protecting interactive surfaces against non-productive cally rather promiscuous. This apparent conundrum interactions. Through such inter actions, molecular chap- is resolved by the fact that HSP70s do not work alone, erones aid in the folding of nascent proteins as they are but rather as ‘HSP70 machines’, collaborating with synthesized by ribosomes, drive protein transport across and being regulated by several cofactors.
    [Show full text]
  • BAG3 and SYNPO (Synaptopodin) Facilitate Phospho-MAPT/Tau Degradation Via Autophagy In
    ManuscriptbioRxiv - with preprint full author doi: https://doi.org/10.1101/518597 details ; this version posted January 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes Changyi Ji1, #, Maoping Tang1, #, Claudia Zeidler2, Jörg Höhfeld2 and Gail VW Johnson1, * 1 Department of Anesthesiology, University of Rochester, 601 Elmwood Ave, Box 604, Rochester, NY 14642, USA; 2 Institute for Cell Biology, University of Bonn, Ulrich-Haberland- Str. 61a, D-53121 Bonn, Germany # Contributed equally to this work *Corresponding Author: Gail V.W. Johnson: [email protected] Voice: +1-585-276-3740; ORCID: 0000-0003-3464-0404 Emails: Jörg Höhfeld – [email protected] Changyi Ji – [email protected] Maoping Tang – [email protected] Claudia Zeidler – [email protected] Key words: autophagosome, postsynaptic density, PPxY domain, SQSTM1/p62, synapse, WW domain Disclosure of Interest: The authors report no conflict of interest. Funding: This work was supported by NIH grant NS098769 to G.V.W.J. and DFG grant HO 1518/8-2 to J.H. 1 bioRxiv preprint doi: https://doi.org/10.1101/518597; this version posted January 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
    [Show full text]
  • Geneseq®: Cardio
    LabCorp GeneSeq®: Cardio Helping you provide better patient care Testing for more than 100 genetic causes of familial cardiac disease. Treatment That May Help Clinical Utility Familial cardiac diseases are associated with up to 80% • Establish/confirm a diagnosis of familial cardiac disease. of cases of sudden cardiac death in young patients.1 • Identify the need for regular cardiac screening, lifestyle Identification of individuals with pathogenic mutations in changes, or pharmacological or surgical intervention to genes associated with cardiac disease may allow timely prevent the progression of cardiac disease and secondary initiation of screening and treatment that may help prevent complications. myocardial infarction, stroke, and sudden cardiac death. • Identify first-degree relatives of the proband who have inherited a disease-causing genetic variant and may be GeneSeq: Cardio at risk for myocardial infarction, stroke, or sudden cardiac death. can be a useful prognostic tool in the presence of a positive • Facilitate appropriate genetic counseling for probands family history and symptoms of cardiomyopathy, arrhythmia, and their first-degree relatives. aortopathy, Noonan syndrome, RASopathies, congenital heart disease, early-onset coronary artery disease, or familial hypercholesterolemia. Sample Requirements • 10 mL whole blood or 30 mL if ordering multiple tests. Six indications for testing, available separately or in combination Test No. Test Name Genes Included In the Profile 451422 GeneSeq®: Cardio - Familial Cardiomyopathy Profile
    [Show full text]
  • LOXL1 Confers Antiapoptosis and Promotes Gliomagenesis Through Stabilizing BAG2
    Cell Death & Differentiation (2020) 27:3021–3036 https://doi.org/10.1038/s41418-020-0558-4 ARTICLE LOXL1 confers antiapoptosis and promotes gliomagenesis through stabilizing BAG2 1,2 3 4 3 4 3 1 1 Hua Yu ● Jun Ding ● Hongwen Zhu ● Yao Jing ● Hu Zhou ● Hengli Tian ● Ke Tang ● Gang Wang ● Xiongjun Wang1,2 Received: 10 January 2020 / Revised: 30 April 2020 / Accepted: 5 May 2020 / Published online: 18 May 2020 © The Author(s) 2020. This article is published with open access Abstract The lysyl oxidase (LOX) family is closely related to the progression of glioma. To ensure the clinical significance of LOX family in glioma, The Cancer Genome Atlas (TCGA) database was mined and the analysis indicated that higher LOXL1 expression was correlated with more malignant glioma progression. The functions of LOXL1 in promoting glioma cell survival and inhibiting apoptosis were studied by gain- and loss-of-function experiments in cells and animals. LOXL1 was found to exhibit antiapoptotic activity by interacting with multiple antiapoptosis modulators, especially BAG family molecular chaperone regulator 2 (BAG2). LOXL1-D515 interacted with BAG2-K186 through a hydrogen bond, and its lysyl 1234567890();,: 1234567890();,: oxidase activity prevented BAG2 degradation by competing with K186 ubiquitylation. Then, we discovered that LOXL1 expression was specifically upregulated through the VEGFR-Src-CEBPA axis. Clinically, the patients with higher LOXL1 levels in their blood had much more abundant BAG2 protein levels in glioma tissues. Conclusively, LOXL1 functions as an important mediator that increases the antiapoptotic capacity of tumor cells, and approaches targeting LOXL1 represent a potential strategy for treating glioma.
    [Show full text]
  • The Interplay Between Bag-1, Hsp70, and Hsp90 Reveals That Inhibiting Hsp70 Rebinding Is Essential for Glucocorticoid Receptor Activity
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.03.075523; this version posted May 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The interplay between Bag-1, Hsp70, and Hsp90 reveals that inhibiting Hsp70 rebinding is essential for Glucocorticoid Receptor activity Authors: Elaine Kirschke, Zygy Roe-Zurz, Chari Noddings, and David Agard Affiliations: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA Keywords: Glucocorticoid Receptor, Hsp90, Hsp70, Bag-1, nucleotide exchange factor Author contributions: Z.R.Z. carried out Hsp70 nucleotide dissociation experiments. E.K. carried out GRLBD ligand binding experiments and assembled all the data. E.K. and D.A.A. wrote the manuscript. Abstract The glucocorticoid receptor (GR), like many signaling proteins requires Hsp90 for sustained activity. Previous biochemical studies revealed that the requirement for Hsp90 is explained by its ability to reverse Hsp70-mediated inactivation of GR through a complex process requiring both cochaperones and Hsp90 ATP hydrolysis. How ATP hydrolysis on Hsp90 enables GR reactivation is unknown. The canonical mechanism of client release from Hsp70 requires ADP:ATP exchange, which is normally rate limiting. Here we show that independent of ATP hydrolysis, Hsp90 acts as an Hsp70 nucleotide exchange factor (NEF) to accelerate ADP dissociation, likely coordinating GR transfer from Hsp70 to Hsp90. As Bag-1 is a canonical Hsp70 NEF that can also reactivate Hsp70:GR, the impact of these two NEFs was compared. Simple acceleration of Hsp70:GR release was insufficient for GR reactivation as Hsp70 rapidly re-binds and re-inactivates GR.
    [Show full text]
  • Associated Athanogene (BAG) Protein Family in Rice
    African Journal of Biotechnology Vol. 11(1), pp. 88-99, 3 January, 2012 Available online at http://www.academicjournals.org/AJB DOI: 10.5897/AJB11.3474 ISSN 1684–5315 © 2012 Academic Journals Full Length Research Paper Identification and characterization of the Bcl-2- associated athanogene (BAG) protein family in rice Rashid Mehmood Rana 1, 2 , Shinan Dong 1, Zulfiqar Ali 3, Azeem Iqbal Khan 4 and Hong Sheng Zhang 1* 1State Key Laboratory of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing 210095, China. 2Department of Plant Breeding and Genetics, PMAS-Arid Agriculture University Rawalpindi, Pakistan. 3Department of Plant Breeding and Genetics, University of Agriculture, Faisalabad-38040, Pakistan. 4Centre of Agricultural Biochemistry and Biotechnology (CABB), University of Agriculture, Faisalabad-38040, Pakistan. Accepted 9 December, 2011 The Bcl-2-associated athanogene (BAG) proteins are involved in the regulation of Hsp70/HSC70 in animals. There are six BAG genes in human that encode nine isoforms with different subcellular locations. Arabidopsis thaliana is reported to contain seven BAG proteins. We searched BAG proteins in Oryza sativa using profile-sequence (Pfam) and profile-profile (FFAS) algorithms and found six homologs. The BAG protein family in O. sativa can be grouped into two classes based on the presence of other conserved domains. Class I consists of four OsBAG genes (1 to 4) containing an additional ubiquitin-like domain, structurally similar to the human BAG1 proteins and might be BAG1 orthologs in plants. Class II consists of two OsBAG genes (5 and 6) containing calmodulin-binding domain. Multiple sequence alignment and structural models of O.
    [Show full text]