Reprogramming of cardiac phosphoproteome, proteome, and transcriptome confers resilience to chronic adenylyl cyclase-driven stress.
AC-cAMP-PKA-Ca2+ signaling
PI3K/AKT signaling pathway
adenylyl cyclase 8
cell biology
computational biology
left ventricle
mouse
phosphoproteome
proteome
systems biology
transcriptome
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
22 Jan 2024
22 Jan 2024
Historique:
medline:
23
1
2024
pubmed:
22
1
2024
entrez:
22
1
2024
Statut:
epublish
Résumé
Our prior study (Tarasov et al., 2022) discovered that numerous adaptive mechanisms emerge in response to cardiac-specific overexpression of adenylyl cyclase type 8 (TGAC8) which included overexpression of a large number of proteins. Here, we conducted an unbiased phosphoproteomics analysis in order to determine the role of altered protein phosphorylation in the adaptive heart performance and protection profile of adult TGAC8 left ventricle (LV) at 3-4 months of age, and integrated the phosphoproteome with transcriptome and proteome. Based on differentially regulated phosphoproteins by genotype, numerous stress-response pathways within reprogrammed TGAC8 LV, including PKA, PI3K, and AMPK signaling pathways, predicted upstream regulators (e.g. PDPK1, PAK1, and PTK2B), and downstream functions (e.g. cell viability, protein quality control), and metabolism were enriched. In addition to PKA, numerous other kinases and phosphatases were hyper-phosphorylated in TGAC8 vs. WT. Hyper-phosphorylated transcriptional factors in TGAC8 were associated with increased mRNA transcription, immune responses, and metabolic pathways. Combination of the phosphoproteome with its proteome and with the previously published TGAC8 transcriptome enabled the elucidation of cardiac performance and adaptive protection profiles coordinately regulated at post-translational modification (PTM) (phosphorylation), translational, and transcriptional levels. Many stress-response signaling pathways, i.e., PI3K/AKT, ERK/MAPK, and ubiquitin labeling, were consistently enriched and activated in the TGAC8 LV at transcriptional, translational, and PTM levels. Thus, reprogramming of the cardiac phosphoproteome, proteome, and transcriptome confers resilience to chronic adenylyl cyclase-driven stress. We identified numerous pathways/function predictions via gene sets, phosphopeptides, and phosphoproteins, which may point to potential novel therapeutic targets to enhance heart adaptivity, maintaining heart performance while avoiding cardiac dysfunction.
Identifiants
pubmed: 38251682
doi: 10.7554/eLife.88732
pii: 88732
doi:
pii:
Substances chimiques
Proteome
0
Adenylyl Cyclases
EC 4.6.1.1
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Phosphoproteins
0
PDPK1 protein, human
EC 2.7.11.1
3-Phosphoinositide-Dependent Protein Kinases
EC 2.7.11.1
Banques de données
GEO
['GSE205234']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
JQ, KC, KT, DR, MP, AS, EL No competing interests declared
Références
Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):E2979-88
pubmed: 23045700
Basic Res Cardiol. 2008 Jan;103(1):22-30
pubmed: 18034275
Bioinformatics. 2002 Apr;18(4):608-16
pubmed: 12016058
Front Mol Neurosci. 2018 Aug 30;11:255
pubmed: 30214393
Genome Res. 2004 Jun;14(6):1188-90
pubmed: 15173120
J Biol Chem. 2003 Aug 15;278(33):30821-7
pubmed: 12799359
Mol Endocrinol. 2007 Oct;21(10):2311-9
pubmed: 17536004
Nat Cell Biol. 2019 Dec;21(12):1553-1564
pubmed: 31768048
iScience. 2019 Jul 26;17:155-166
pubmed: 31279933
J Clin Invest. 2004 Jun;113(11):1535-49
pubmed: 15173880
Diabetologia. 2015 Apr;58(4):749-57
pubmed: 25403481
Cell Commun Signal. 2017 Jun 21;15(1):23
pubmed: 28637459
Cardiovasc Res. 2008 Jan 15;77(2):256-64
pubmed: 18006480
EMBO Rep. 2003 Apr;4(4):368-73
pubmed: 12671680
Cell. 1995 Jul 28;82(2):241-50
pubmed: 7543024
Drug Discov Today. 2014 Jul;19(7):956-62
pubmed: 24662036
Nat Commun. 2014 Aug 19;5:4687
pubmed: 25134617
Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10849-E10858
pubmed: 30373812
FASEB J. 2002 Oct;16(12):1636-8
pubmed: 12206999
Pharmacol Ther. 2015 Apr;148:114-31
pubmed: 25435019
Oncogene. 2000 May 15;19(21):2628-37
pubmed: 10851062
Cancer Cells. 1990 Nov;2(11):337-44
pubmed: 2149275
Arterioscler Thromb Vasc Biol. 2009 Aug;29(8):1207-12
pubmed: 19461052
Biochim Biophys Acta. 2011 Jun;1813(6):1190-7
pubmed: 21419810
Circ Res. 2009 Jun 5;104(11):1240-52
pubmed: 19498210
Chin Med J (Engl). 2022 May 5;135(9):1036-1038
pubmed: 35067563
Nat Rev Mol Cell Biol. 2001 Aug;2(8):599-609
pubmed: 11483993
Biochem Biophys Res Commun. 2001 Jun 8;284(2):485-9
pubmed: 11394906
J Immunol. 2009 Jul 15;183(2):856-64
pubmed: 19542364
Nucleic Acids Res. 2019 Jan 8;47(D1):D506-D515
pubmed: 30395287
Curr Top Membr. 2010;66:91-113
pubmed: 21666757
Front Neurosci. 2019 Jun 18;13:615
pubmed: 31275103
Circ Res. 2000 Apr 14;86(7):795-801
pubmed: 10764414
Elife. 2022 Dec 14;11:
pubmed: 36515265
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2598-603
pubmed: 20133737
J Exp Bot. 2018 Aug 31;69(19):4583-4590
pubmed: 29846689
Cells. 2022 Nov 04;11(21):
pubmed: 36359893
Blood. 2013 May 2;121(18):3718-26
pubmed: 23444402
Nat Methods. 2009 Nov;6(11):786-7
pubmed: 19876014
J Proteome Res. 2008 Dec;7(12):5314-26
pubmed: 19367708
J Biol Chem. 1989 Jul 5;264(19):11468-74
pubmed: 2544595
J Cell Sci. 2012 Dec 1;125(Pt 23):5850-9
pubmed: 22976297
Circ Res. 2015 Jan 2;116(1):138-49
pubmed: 25552693