Resolving titin's lifecycle and the spatial organization of protein turnover in mouse cardiomyocytes.
STED microscopy
live imaging
proteostasis
sarcomere
titin
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
10 12 2019
10 12 2019
Historique:
pubmed:
24
11
2019
medline:
9
4
2020
entrez:
24
11
2019
Statut:
ppublish
Résumé
Cardiac protein homeostasis, sarcomere assembly, and integration of titin as the sarcomeric backbone are tightly regulated to facilitate adaptation and repair. Very little is known on how the >3-MDa titin protein is synthesized, moved, inserted into sarcomeres, detached, and degraded. Here, we generated a bifluorescently labeled knockin mouse to simultaneously visualize both ends of the molecule and follow titin's life cycle in vivo. We find titin mRNA, protein synthesis and degradation compartmentalized toward the Z-disk in adult, but not embryonic cardiomyocytes. Originating at the Z-disk, titin contributes to a soluble protein pool (>15% of total titin) before it is integrated into the sarcomere lattice. Titin integration, disintegration, and reintegration are stochastic and do not proceed sequentially from Z-disk to M-band, as suggested previously. Exchange between soluble and integrated titin depends on titin protein composition and differs between individual cardiomyocytes. Thus, titin dynamics facilitate embryonic vs. adult sarcomere remodeling with implications for cardiac development and disease.
Identifiants
pubmed: 31757849
pii: 1904385116
doi: 10.1073/pnas.1904385116
pmc: PMC6911189
doi:
Substances chimiques
Protein Kinases
EC 2.7.-
titin protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
25126-25136Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL123078
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
Références
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9493-8
pubmed: 9256510
Cell Motil Cytoskeleton. 2008 Jan;65(1):40-58
pubmed: 17948234
N Engl J Med. 2016 Jan 21;374(3):233-41
pubmed: 26735901
Nat Rev Mol Cell Biol. 2015 Mar;16(3):167-77
pubmed: 25693130
Science. 2005 Jun 10;308(5728):1599-603
pubmed: 15802564
Dev Biol. 2003 May 15;257(2):382-94
pubmed: 12729566
PLoS Genet. 2010 Nov 18;6(11):e1001208
pubmed: 21124995
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
J Cell Biol. 1998 Nov 16;143(4):1013-27
pubmed: 9817758
Circ Res. 2000 Jan 7-21;86(1):59-67
pubmed: 10625306
Elife. 2015 Oct 16;4:e09406
pubmed: 26473617
J Cell Biochem. 2012 Apr;113(4):1265-73
pubmed: 22105831
EMBO J. 2018 Jan 4;37(1):139-159
pubmed: 29146773
J Mol Med (Berl). 2016 Dec;94(12):1349-1358
pubmed: 27889803
Cell Motil Cytoskeleton. 2000 Jan;45(1):67-82
pubmed: 10618168
Cell Struct Funct. 1997 Feb;22(1):51-8
pubmed: 9113390
Proc Natl Acad Sci U S A. 1979 Aug;76(8):3698-702
pubmed: 291034
Circ Res. 2001 Nov 23;89(11):1065-72
pubmed: 11717165
Mol Biol Cell. 1997 Apr;8(4):705-17
pubmed: 9247649
J Cell Biol. 1984 Dec;99(6):2268-78
pubmed: 6438115
PLoS One. 2015 Jun 15;10(6):e0129176
pubmed: 26076379
Cell Motil Cytoskeleton. 1994;28(1):1-24
pubmed: 8044846
J Cell Biol. 2011 May 16;193(4):785-98
pubmed: 21555460
J Cell Biol. 1990 Apr;110(4):1159-72
pubmed: 2108970
Nat Commun. 2017 Oct 19;8(1):1041
pubmed: 29051486
EMBO J. 1997 Jan 15;16(2):211-20
pubmed: 9029142
J Biol Chem. 2003 Feb 21;278(8):6059-65
pubmed: 12464612
Dev Biol. 2008 Jun 15;318(2):236-46
pubmed: 18455713
J Cell Sci. 1999 Nov;112 ( Pt 22):4101-12
pubmed: 10547369
Nature. 2018 Nov;563(7732):508-513
pubmed: 30464263
N Engl J Med. 2012 Feb 16;366(7):619-28
pubmed: 22335739
Nat Med. 2012 May;18(5):766-73
pubmed: 22466703