WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.
Adolescent
Adult
Aged
Animals
Cardiomyopathies
/ genetics
Extracellular Matrix Proteins
/ metabolism
Female
Fibrosis
/ genetics
Gene Expression Regulation
Gene Regulatory Networks
Genetic Predisposition to Disease
/ genetics
Heart Diseases
/ genetics
Humans
Male
Mice
Mice, Transgenic
Middle Aged
Protein Isoforms
Smad2 Protein
/ genetics
Transforming Growth Factor beta
/ metabolism
Ubiquitin-Protein Ligases
/ genetics
Young Adult
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 08 2019
09 08 2019
Historique:
received:
10
10
2018
accepted:
19
07
2019
entrez:
11
8
2019
pubmed:
11
8
2019
medline:
18
12
2019
Statut:
epublish
Résumé
Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
Identifiants
pubmed: 31399586
doi: 10.1038/s41467-019-11551-9
pii: 10.1038/s41467-019-11551-9
pmc: PMC6689010
doi:
Substances chimiques
Extracellular Matrix Proteins
0
Protein Isoforms
0
Smad2 Protein
0
Smad2 protein, mouse
0
Transforming Growth Factor beta
0
betaIG-H3 protein
148710-76-3
Wwp2 protein, mouse
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3616Subventions
Organisme : British Heart Foundation
ID : SP/10/10/28431
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U120097112
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/11/25/28740
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/15/5/31446
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/1992027/7163
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U120085815
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Références
Genetics. 2011 Dec;189(4):1449-59
pubmed: 21926303
Cardiovasc Res. 2000 May;46(2):307-15
pubmed: 10773235
Brief Funct Genomics. 2014 Jan;13(1):66-78
pubmed: 23960099
Cardiovasc Res. 2013 Mar 15;97(4):653-65
pubmed: 23118132
Eur Heart J. 2010 May;31(10):1188-96
pubmed: 20031959
J Clin Invest. 2005 Mar;115(3):599-609
pubmed: 15711638
J Clin Invest. 2017 Oct 2;127(10):3770-3783
pubmed: 28891814
PLoS Genet. 2007 Sep;3(9):1724-35
pubmed: 17907809
Int J Sports Med. 2018 Apr;39(4):314-321
pubmed: 29534260
JAMA. 2013 Mar 6;309(9):896-908
pubmed: 23462786
Curr Cancer Drug Targets. 2011 Mar;11(3):347-56
pubmed: 21247385
EMBO J. 2011 Nov 01;30(23):4777-89
pubmed: 22045334
Matrix Biol. 2018 Aug;68-69:8-27
pubmed: 29355590
Bioinformatics. 2009 Nov 1;25(21):2780-6
pubmed: 19689953
Nature. 2010 Sep 23;467(7314):460-4
pubmed: 20827270
Heart Fail Clin. 2018 Apr;14(2):139-146
pubmed: 29525643
Nat Cell Biol. 2011 Sep 25;13(11):1368-75
pubmed: 21947082
Circ Res. 2016 Mar 18;118(6):1021-40
pubmed: 26987915
Nat Commun. 2015 Jan 23;6:6031
pubmed: 25615886
Nat Cell Biol. 2011 Jan;13(1):59-65
pubmed: 21170031
Nat Cell Biol. 2011 Jun;13(6):728-33
pubmed: 21532586
Nature. 2017 Dec 7;552(7683):110-115
pubmed: 29160304
Mol Cell Biol. 2005 Nov;25(22):9845-58
pubmed: 16260601
Bioinformatics. 2010 Oct 1;26(19):2438-44
pubmed: 20709693
Nat Rev Mol Cell Biol. 2004 Mar;5(3):209-19
pubmed: 14991001
Nat Genet. 2005 Mar;37(3):243-53
pubmed: 15711544
BMC Bioinformatics. 2007 Jun 25;8:220
pubmed: 17592643
Methods Mol Biol. 2017;1488:337-362
pubmed: 27933533
Genome Res. 2014 Jun;24(6):942-53
pubmed: 24793478
Nat Genet. 2008 May;40(5):546-52
pubmed: 18443592
N Engl J Med. 2015 Mar 19;372(12):1138-49
pubmed: 25785971
Cell. 2007 Jan 12;128(1):141-56
pubmed: 17218261
J Biol Chem. 2003 Sep 19;278(38):35857-60
pubmed: 12860974
J Cardiovasc Pharmacol. 2011 Apr;57(4):376-9
pubmed: 21297493
Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5115-20
pubmed: 23479606
Oncoscience. 2014 Nov 28;1(12):807-20
pubmed: 25621296
Genome Biol. 2017 Sep 14;18(1):170
pubmed: 28903782
Cell Immunol. 2016 Aug-Sep;306-307:1-8
pubmed: 27406900
Nat Genet. 2008 Aug;40(8):952-4
pubmed: 18587397
JCI Insight. 2016 May 5;1(6):
pubmed: 27239561
Cell Res. 2016 Apr;26(4):484-98
pubmed: 27002218
Nat Genet. 2018 Dec;50(12):1681-1687
pubmed: 30374069
EMBO J. 2000 Apr 17;19(8):1745-54
pubmed: 10775259
Oncol Rep. 2017 Aug;38(2):933-940
pubmed: 28627672
Sci Transl Med. 2018 Apr 11;10(436):
pubmed: 29643228
Cells. 2014 Oct 15;3(4):981-93
pubmed: 25317929
Biomater Res. 2016 May 25;20:13
pubmed: 27226899
Eur J Heart Fail. 2017 Feb;19(2):177-191
pubmed: 28157267
Mol Cell. 2002 Aug;10(2):283-94
pubmed: 12191474
J Biol Chem. 2007 Aug 3;282(31):22804-15
pubmed: 17500067
Front Med (Lausanne). 2015 Sep 03;2:59
pubmed: 26389119
J Invest Dermatol. 2015 Jul;135(7):1893-1902
pubmed: 25739049
J Cell Biol. 2011 Aug 8;194(3):355-65
pubmed: 21825071
Cell Res. 2009 Jan;19(1):36-46
pubmed: 19114992
Oncogene. 2011 May 26;30(21):2451-62
pubmed: 21258410
Nat Commun. 2011;2:251
pubmed: 21427722
Cardiovasc Res. 2007 May 1;74(2):207-12
pubmed: 16919613
Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6614-9
pubmed: 17420471
Cell Biosci. 2011 Dec 28;1(1):43
pubmed: 22204598
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Fibrogenesis Tissue Repair. 2011 Feb 01;4(1):4
pubmed: 21284856
PLoS One. 2017 Jul 27;12(7):e0181945
pubmed: 28750100
Int J Biochem Cell Biol. 2008;40(3):383-408
pubmed: 18061509
Cell Rep. 2014 Aug 21;8(4):1210-24
pubmed: 25131209
Nat Med. 2015 Sep;21(9):998-1009
pubmed: 26236991
Basic Res Cardiol. 2013 Jan;108(1):316
pubmed: 23197152
Dev Dyn. 2010 Jun;239(6):1573-84
pubmed: 20503355
Circ Res. 2010 Jun 11;106(11):1675-80
pubmed: 20538689
Mol Pharmacol. 2002 Jul;62(1):65-74
pubmed: 12065756
Nat Cell Biol. 1999 Dec;1(8):472-8
pubmed: 10587642
JCI Insight. 2017 May 4;2(9):
pubmed: 28469078
Nat Rev Genet. 2011 Sep 07;12(10):671-82
pubmed: 21897427
Cardiovasc Pathol. 2016 May-Jun;25(3):225-231
pubmed: 26938796
J Cardiovasc Transl Res. 2013 Dec;6(6):931-44
pubmed: 23929067
Am J Physiol Heart Circ Physiol. 2013 Jun 15;304(12):H1719-26
pubmed: 23585135
Heart Fail Rev. 2014 Mar;19(2):173-85
pubmed: 23124941
J Biol Chem. 2015 Oct 16;290(42):25427-38
pubmed: 26318453
Cardiovasc Ther. 2012 Feb;30(1):e30-40
pubmed: 21883991
Circ Res. 2015 Mar 27;116(7):1269-76
pubmed: 25814687