Latent TGFβ complexes are transglutaminase cross-linked to fibrillin to facilitate TGFβ activation.
LTBP
TGFbeta activation
fibrillin
transglutaminase-2
Journal
Matrix biology : journal of the International Society for Matrix Biology
ISSN: 1569-1802
Titre abrégé: Matrix Biol
Pays: Netherlands
ID NLM: 9432592
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
08
09
2021
revised:
21
01
2022
accepted:
25
01
2022
pubmed:
6
2
2022
medline:
25
3
2022
entrez:
5
2
2022
Statut:
ppublish
Résumé
TGFβ superfamily members are potent growth factors in the extracellular matrix with essential roles in all aspects of cellular behaviour. Latent TGFβ binding proteins (LTBPs) are co-expressed with TGFβ, essential for correct folding and secretion of the growth factor, to form large latent complexes. These large latent complexes bind extracellular proteins such as fibrillin for sequestration of TGFβ in the matrix, essential for normal tissue function, and dysregulated TGFβ signalling is a hallmark of many fibrillinopathies. Transglutaminase-2 (TG2) cross-linking of LTBPs is known to play a role in TGFβ activation but the underlying molecular mechanisms are not resolved. Here we show that fibrillin is a matrix substrate for TG2 and that TG2 cross-linked complexes can be formed between fibrillin and LTBP-1 and -3, and their latent TGFβ complexes. The structure of the fibrillin-LTBP1 complex shows that the two elongated proteins interact in a perpendicular arrangement which would allow them to form distal interactions between the matrix and the cell surface. Formation of the cross-link with fibrillin does not change the interaction between latent TGFβ and integrin αVβ6 but does increase TGFβ activation in cell-based assays. The activating effect may be due to direction of the latent complexes to the cell surface by fibrillin, as competition with heparan sulphate can ameliorate the activating effect. Together, these data support that TGFβ activation can be enhanced by covalent tethering of LTBPs to the matrix via fibrillin.
Identifiants
pubmed: 35122964
pii: S0945-053X(22)00010-5
doi: 10.1016/j.matbio.2022.01.005
pmc: PMC8932414
pii:
doi:
Substances chimiques
Fibrillin-1
0
Fibrillin-2
0
Fibrillins
0
Latent TGF-beta Binding Proteins
0
Microfilament Proteins
0
Transforming Growth Factor beta
0
Transglutaminases
EC 2.3.2.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
24-39Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R008221/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S015779/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L016540/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203128/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
Références
Mol Cell Biol. 2001 Jan;21(1):148-55
pubmed: 11113189
ScientificWorldJournal. 2014 Mar 23;2014:714561
pubmed: 24778599
J Med Genet. 2006 Oct;43(10):769-87
pubmed: 16571647
PLoS One. 2012;7(10):e48629
pubmed: 23119075
Structure. 2017 Aug 1;25(8):1208-1221.e5
pubmed: 28669633
J Biol Chem. 2005 Aug 26;280(34):30526-37
pubmed: 15980072
Biochemistry. 2005 Aug 2;44(30):10271-81
pubmed: 16042404
J Biol Chem. 2003 Jan 24;278(4):2750-7
pubmed: 12429738
J Cell Biol. 1997 Mar 10;136(5):1151-63
pubmed: 9060478
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18758-63
pubmed: 19022904
Nature. 2011 Jun 15;474(7351):343-9
pubmed: 21677751
J Cell Sci. 2010 Sep 1;123(Pt 17):3006-18
pubmed: 20699357
J Cell Sci. 2018 Mar 1;131(5):
pubmed: 29361522
J Biol Chem. 2009 Jun 19;284(25):16872-16881
pubmed: 19349279
Biochemistry. 1997 Dec 16;36(50):15841-7
pubmed: 9398316
J Biol Chem. 2008 Oct 3;283(40):27017-27
pubmed: 18669635
Structure. 2013 Oct 8;21(10):1743-56
pubmed: 24035709
PLoS One. 2014 Jan 29;9(1):e87125
pubmed: 24489852
J Cell Physiol. 2011 Jun;226(6):1499-509
pubmed: 20945348
Biophys J. 1999 Jun;76(6):2879-86
pubmed: 10354416
Curr Opin Struct Biol. 2012 Oct;22(5):583-90
pubmed: 22841476
Mol Biol Cell. 2000 Aug;11(8):2691-704
pubmed: 10930463
Matrix Biol. 2015 Sep;47:3-12
pubmed: 25957947
Matrix Biol. 2019 Nov;84:17-30
pubmed: 31226403
J Cell Biol. 2004 Jun 7;165(5):723-34
pubmed: 15184403
FASEB J. 2005 Nov;19(13):1798-808
pubmed: 16260650
Nature. 2021 Aug;596(7873):583-589
pubmed: 34265844
J Biol Chem. 2001 Jun 8;276(23):20673-8
pubmed: 11274171
Biochem J. 2005 May 15;388(Pt 1):1-5
pubmed: 15790312
J Biol Chem. 1996 Nov 22;271(47):29891-6
pubmed: 8939931
Nature. 2017 Feb 2;542(7639):55-59
pubmed: 28117447
J Histochem Cytochem. 1999 Nov;47(11):1417-32
pubmed: 10544215
J Appl Crystallogr. 2021 Feb 01;54(Pt 1):343-355
pubmed: 33833657
J Cell Physiol. 2009 Apr;219(1):14-22
pubmed: 19016471
J Cell Sci. 2007 Apr 15;120(Pt 8):1383-92
pubmed: 17374638
J Biol Chem. 1994 Nov 11;269(45):28443-9
pubmed: 7961786
J Biol Chem. 2001 Sep 21;276(38):36035-42
pubmed: 11461921
Drug Discov Today. 2018 Mar;23(3):575-591
pubmed: 29362136
Curr Biol. 2011 Dec 20;21(24):2046-54
pubmed: 22169532
EMBO J. 1996 Jan 15;15(2):245-53
pubmed: 8617200
J Cell Biol. 1993 Apr;121(2):439-48
pubmed: 8096847
J Biol Chem. 2007 Sep 7;282(36):26418-30
pubmed: 17580303
Hum Mol Genet. 2014 Nov 1;23(21):5672-82
pubmed: 24908666
J Cell Biol. 2002 Jan 21;156(2):227-32
pubmed: 11790802
Bioinformatics. 2018 Jun 1;34(11):1944-1946
pubmed: 29300836
J Mol Biol. 2020 Oct 2;432(21):5736-5751
pubmed: 32898582
J Cell Sci. 2001 Jan;114(Pt 1):187-197
pubmed: 11112702
Semin Cell Dev Biol. 2019 May;89:109-117
pubmed: 30016650
J Biol Chem. 2005 May 13;280(19):18871-80
pubmed: 15677465
Sci Rep. 2016 Sep 28;6:34347
pubmed: 27677855
Sci Rep. 2016 Oct 25;6:35956
pubmed: 27779234
Sci Rep. 2017 Mar 02;7:43714
pubmed: 28252045
J Bone Miner Res. 2000 Jan;15(1):68-81
pubmed: 10646116