DUX4 expression activates JNK and p38 MAP kinases in myoblasts.
MAP kinase signaling
Muscular dystrophy
Phosphoproteomics
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 11 2022
01 11 2022
Historique:
received:
12
02
2022
accepted:
28
09
2022
pubmed:
6
10
2022
medline:
2
11
2022
entrez:
5
10
2022
Statut:
ppublish
Résumé
Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of the DUX4 transcription factor in skeletal muscle that results in transcriptional alterations, abnormal phenotypes and cell death. To gain insight into the kinetics of DUX4-induced stresses, we activated DUX4 expression in myoblasts and performed longitudinal RNA sequencing paired with proteomics and phosphoproteomics. This analysis revealed changes in cellular physiology upon DUX4 activation, including DNA damage and altered mRNA splicing. Phosphoproteomic analysis uncovered rapid widespread changes in protein phosphorylation following DUX4 induction, indicating that alterations in kinase signaling might play a role in DUX4-mediated stress and cell death. Indeed, we demonstrate that two stress-responsive MAP kinase pathways, JNK and p38, are activated in response to DUX4 expression. Inhibition of each of these pathways ameliorated DUX4-mediated cell death in myoblasts. These findings uncover that the JNK pathway is involved in DUX4-mediated cell death and provide additional insights into the role of the p38 pathway, a clinical target for the treatment of FSHD.
Identifiants
pubmed: 36196640
pii: 277066
doi: 10.1242/dmm.049516
pmc: PMC10655719
pii:
doi:
Substances chimiques
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Homeodomain Proteins
0
Banques de données
Dryad
['10.5061/dryad.k0p2ngfbh']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2022. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests At the time that these studies were performed, C.M.B., A.S.H., M.S.A., X.L., V.M., S.G., L.X., T.G., A.H., M.M., R.M., J.O., and N.C. were all Pfizer employees and declare potential conflicts of interest due to income received from their employment.
Références
Hum Mol Genet. 2016 Oct 15;25(20):4419-4431
pubmed: 28171552
Biochim Biophys Acta. 2007 Aug;1773(8):1341-8
pubmed: 17306896
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
pubmed: 11717429
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10541-6
pubmed: 9724739
Nat Genet. 2012 Dec;44(12):1370-4
pubmed: 23143600
Cancer Lett. 2020 Oct 28;491:70-77
pubmed: 32735910
Neuron. 1999 Apr;22(4):667-76
pubmed: 10230788
Methods Mol Biol. 2010;661:3-38
pubmed: 20811974
PLoS One. 2016 Jul 28;11(7):e0160022
pubmed: 27467759
Biochem J. 2009 Jan 1;417(1):15-27
pubmed: 19061484
JCI Insight. 2021 Jun 22;6(12):
pubmed: 34156029
J Am Soc Mass Spectrom. 1994 Nov;5(11):976-89
pubmed: 24226387
PLoS Genet. 2017 Mar 8;13(3):e1006658
pubmed: 28273136
Nature. 2000 May 4;405(6782):91-4
pubmed: 10811224
J Enzyme Inhib Med Chem. 2020 Dec;35(1):574-583
pubmed: 31994958
Science. 2010 Sep 24;329(5999):1650-3
pubmed: 20724583
Genes Dev. 2003 Aug 15;17(16):1969-78
pubmed: 12893778
Oncogene. 2007 May 14;26(22):3159-71
pubmed: 17496913
Skelet Muscle. 2020 Apr 11;10(1):8
pubmed: 32278354
Dis Model Mech. 2022 Nov 1;15(11):
pubmed: 36196640
J Pharmacol Exp Ther. 2019 Aug;370(2):219-230
pubmed: 31189728
Dev Cell. 2012 Jan 17;22(1):38-51
pubmed: 22209328
J Exp Med. 2005 Jan 17;201(2):279-89
pubmed: 15642743
Nat Commun. 2018 Aug 2;9(1):3030
pubmed: 30072727
J Biol Chem. 2004 Mar 12;279(11):10442-9
pubmed: 14688258
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Hum Mutat. 2009 Oct;30(10):1449-59
pubmed: 19728363
Ann Neurol. 2011 Mar;69(3):540-52
pubmed: 21446026
Am J Physiol. 1997 Nov;273(5):L930-40
pubmed: 9374719
Genes Dev. 1993 Nov;7(11):2135-48
pubmed: 8224842
Hum Mol Genet. 2018 Aug 1;27(R2):R153-R162
pubmed: 29718206
Nat Methods. 2007 Nov;4(11):923-5
pubmed: 17952086
Ann Appl Stat. 2016 Jun;10(2):946-963
pubmed: 28367255
Nat Genet. 2017 Jun;49(6):941-945
pubmed: 28459456
Mol Cell Proteomics. 2020 Oct;19(10):1706-1723
pubmed: 32680918
Chem Biol. 2014 Nov 20;21(11):1433-43
pubmed: 25442375
EMBO Rep. 2001 Mar;2(3):222-8
pubmed: 11266364
In Vivo. 2008 May-Jun;22(3):305-9
pubmed: 18610740
Genome Biol. 2010;11(10):R106
pubmed: 20979621
J Pharmacol Exp Ther. 2020 Sep;374(3):489-498
pubmed: 32576599
Immunity. 1999 Dec;11(6):721-31
pubmed: 10626894
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Orphanet J Rare Dis. 2021 Mar 12;16(1):129
pubmed: 33712050
Genome Biol. 2014 Feb 03;15(2):R29
pubmed: 24485249
Mol Cell Biol. 1998 Aug;18(8):4924-34
pubmed: 9671500
Biochem J. 2010 Aug 1;429(3):403-17
pubmed: 20626350
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):89-101
pubmed: 15023353
PLoS One. 2018 Feb 7;13(2):e0192657
pubmed: 29415061
Nat Commun. 2017 Sep 15;8(1):550
pubmed: 28916757
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
J Proteome Res. 2013 Aug 2;12(8):3586-98
pubmed: 23768245
Continuum (Minneap Minn). 2016 Dec;22(6, Muscle and Neuromuscular Junction Disorders):1916-1931
pubmed: 27922500
Nat Genet. 2017 Jun;49(6):925-934
pubmed: 28459457
PLoS Genet. 2013 Nov;9(11):e1003947
pubmed: 24278031
Cold Spring Harb Perspect Biol. 2012 Nov 01;4(11):
pubmed: 23125017
Elife. 2019 Jan 15;8:
pubmed: 30644821
Microbiol Mol Biol Rev. 2011 Mar;75(1):50-83
pubmed: 21372320
Elife. 2015 Jan 07;4:
pubmed: 25564732
Ann Clin Transl Neurol. 2015 Feb;2(2):151-66
pubmed: 25750920
Cancer Res. 1997 Oct 1;57(19):4177-82
pubmed: 9331070
Biochim Biophys Acta. 2007 Aug;1773(8):1358-75
pubmed: 17481747
J Biol Chem. 1999 Feb 19;274(8):5193-200
pubmed: 9988769
PLoS Genet. 2010 Oct 28;6(10):e1001181
pubmed: 21060811
Elife. 2016 Feb 01;5:e11752
pubmed: 26829591
Sci Adv. 2020 Jan 10;6(2):eaax8978
pubmed: 31950079
Nat Rev Drug Discov. 2003 Jul;2(7):554-65
pubmed: 12815381
Oncogene. 2008 Oct 20;27(48):6245-51
pubmed: 18931691
Prog Mol Biol Transl Sci. 2012;106:145-69
pubmed: 22340717
J Appl Physiol (1985). 1999 Nov;87(5):1668-73
pubmed: 10562607
Free Radic Biol Med. 2016 Oct;99:244-258
pubmed: 27519269
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
Redox Biol. 2021 Jul;43:102008
pubmed: 34030118
Nat Genet. 1992 Sep;2(1):26-30
pubmed: 1363881
Cell. 1994 Mar 25;76(6):1025-37
pubmed: 8137421
Hum Mol Genet. 2015 Oct 15;24(20):5901-14
pubmed: 26246499