Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.
N-homocysteinylation
acetyl homocysteine thioether
methionyl-tRNA synthetase
neural tube defects
reactive oxygen species
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
06 03 2020
06 03 2020
Historique:
received:
27
06
2018
revised:
16
12
2019
accepted:
19
12
2019
pubmed:
1
2
2020
medline:
29
7
2021
entrez:
1
2
2020
Statut:
ppublish
Résumé
Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)-homocysteinylation. Here, we identified hundreds of novel N-homocysteinylated proteins. N-homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine-induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid-induced and hyperhomocysteinemia-induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia-associated diseases.
Identifiants
pubmed: 32003121
doi: 10.15252/emmm.201809469
pmc: PMC7059139
doi:
Substances chimiques
Homocysteine
0LVT1QZ0BA
Methionine-tRNA Ligase
EC 6.1.1.10
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9469Subventions
Organisme : The State Key Development Programs (973) of Basic Research of China
ID : 2013CB911204
Pays : International
Organisme : The State Key Development Programs (973) of Basic Research of China
ID : 2013CB531200
Pays : International
Organisme : The State Key Development Programs (973) of Basic Research of China
ID : 2013CB945100
Pays : International
Organisme : The State Key Development Programs (973) of Basic Research of China
ID : 2015AA020913
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : 31330023
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : 81722021
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : 81471454
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : 31671453
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : 81771627
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : 31521003
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : U1432242
Pays : International
Organisme : NSF|Foundation for Innovative Research Groups of the National Natural Science Foundation of China
ID : 31425008
Pays : International
Organisme : 863 Programs of China
ID : 2015AA020913
Pays : International
Organisme : Science and Technology Municipal Commission of Shanghai
ID : 16JC1405300
Pays : International
Organisme : Science and Technology Municipal Commission of Shanghai
ID : 17YF1424200
Pays : International
Organisme : The National Natural Science Foundation of China
ID : 31801167
Pays : International
Organisme : The National Natural Science Foundation of China
ID : 81974175
Pays : International
Organisme : The National Natural Science Foundation of China
ID : 81500977
Pays : International
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Thromb Haemost. 2006 Sep;96(3):342-7
pubmed: 16953277
Am J Clin Nutr. 2005 Jan;81(1):147-53
pubmed: 15640474
J Cell Physiol. 2000 Mar;182(3):311-22
pubmed: 10653597
Hum Mol Genet. 2010 Dec 1;19(23):4560-72
pubmed: 20843827
Cancer Res. 2002 Nov 1;62(21):6240-5
pubmed: 12414653
Nature. 2003 Oct 9;425(6958):633-7
pubmed: 14534590
Nat Rev Neurol. 2011 Jan;7(1):9-10
pubmed: 21221112
Clin Chim Acta. 2002 Aug;322(1-2):21-8
pubmed: 12104077
Amino Acids. 2007;32(4):561-72
pubmed: 17285228
Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a001834
pubmed: 20182622
JAMA. 2007 Jun 6;297(21):2408-9
pubmed: 17551134
Cell Metab. 2018 Jan 9;27(1):151-166.e6
pubmed: 29198988
Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2015;32(8):1287-300
pubmed: 26125677
Am J Hum Genet. 1996 Jan;58(1):17-20
pubmed: 8554053
J Matern Fetal Neonatal Med. 2016 Sep;29(18):2944-8
pubmed: 26479326
Development. 2011 Feb;138(4):667-76
pubmed: 21228006
Circ Res. 2000 Jul 7;87(1):45-51
pubmed: 10884371
Lancet. 1995 Jan 21;345(8943):149-51
pubmed: 7741859
N Engl J Med. 2006 Apr 13;354(15):1578-88
pubmed: 16531614
Org Biomol Chem. 2013 Nov 21;11(43):7606-10
pubmed: 24100405
Dis Model Mech. 2009 Sep-Oct;2(9-10):467-78
pubmed: 19638421
Genes Dev. 2008 Sep 1;22(17):2308-41
pubmed: 18765787
J Mol Biol. 2001 Aug 3;311(1):205-16
pubmed: 11469869
Toxicol In Vitro. 1993 Nov;7(6):743-9
pubmed: 20732275
PLoS One. 2012;7(2):e31388
pubmed: 22319627
Mol Cell Biochem. 2006 Oct;291(1-2):119-26
pubmed: 16715183
J Neurosci. 2014 Aug 13;34(33):10906-23
pubmed: 25122892
Oncogene. 2005 Mar 3;24(10):1794-801
pubmed: 15688027
Blood. 2011 Aug 18;118(7):2007-14
pubmed: 21705496
Ann Clin Biochem. 2009 May;46(Pt 3):231-4
pubmed: 19342442
J Cell Biochem. 2004 May 15;92(2):351-60
pubmed: 15108360
J Nutr. 2003 Nov;133(11 Suppl 1):3731S-3739S
pubmed: 14608107
J Cell Mol Med. 2012 Jul;16(7):1606-17
pubmed: 22004004
Clin Chem Lab Med. 2005;43(10):1011-4
pubmed: 16197290
Reprod Toxicol. 2017 Apr;69:167-173
pubmed: 28242235
J Mol Biol. 2010 Jul 23;400(4):889-907
pubmed: 20510245
J Biol Chem. 1996 Jul 26;271(30):17601-4
pubmed: 8663611
Proc Soc Exp Biol Med. 1976 Nov;153(2):273-6
pubmed: 995958
JAMA. 2004 Feb 4;291(5):565-75
pubmed: 14762035
Nat Protoc. 2010 Sep;5(9):1583-95
pubmed: 21085124
Cell Metab. 2010 Dec 1;12(6):662-7
pubmed: 21109198
Oncogene. 1999 Mar 11;18(10):1781-7
pubmed: 10086332
Diabetes Care. 2010 Sep;33(9):2031-7
pubmed: 20551012
Hum Mol Genet. 2009 Oct 15;18(R2):R113-29
pubmed: 19808787
Annu Rev Neurosci. 2009;32:149-84
pubmed: 19555289
Development. 2014 Jan;141(1):148-57
pubmed: 24284205
J Alzheimers Dis. 2012;30(2):225-31
pubmed: 22406444
Science. 2013 Mar 1;339(6123):1222002
pubmed: 23449594
Cancer Res. 1985 Dec;45(12 Pt 1):6219-24
pubmed: 3840720
J Neurosci. 2000 Sep 15;20(18):6920-6
pubmed: 10995836
Am J Obstet Gynecol. 2008 Jan;198(1):130.e1-7
pubmed: 18166327
EMBO Rep. 2011 Jun;12(6):534-41
pubmed: 21566644
Chem Biol. 2011 Dec 23;18(12):1658-68
pubmed: 22195568
Nucleic Acids Res. 1981 Jul 10;9(13):3105-17
pubmed: 7024910
Free Radic Biol Med. 2002 Aug 1;33(3):337-49
pubmed: 12126755
J Hum Genet. 2012 Aug;57(8):545-51
pubmed: 22673690
Am J Hum Genet. 1998 May;62(5):1044-51
pubmed: 9545395
PLoS Biol. 2012;10(3):e1001288
pubmed: 22448145
Lancet. 2007 Jun 2;369(9576):1841-1842
pubmed: 17544750
J Cell Biochem. 2010 Feb 15;109(3):468-77
pubmed: 19960509
Circulation. 1998 Dec 8;98(23):2520-6
pubmed: 9843457
Nat Cell Biol. 2006 May;8(5):501-8
pubmed: 16604061
EMBO Mol Med. 2020 Mar 6;12(3):e9469
pubmed: 32003121
Thromb Haemost. 2014 Sep 2;112(3):459-65
pubmed: 24816826
Circulation. 1999 Sep 14;100(11):1161-8
pubmed: 10484535
Trends Neurosci. 2003 Mar;26(3):137-46
pubmed: 12591216
Amino Acids. 2012 Sep;43(3):1339-48
pubmed: 22227865
Am J Pathol. 1983 Oct;113(1):117-24
pubmed: 6312802
Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15227-32
pubmed: 8986792
Birth Defects Res A Clin Mol Teratol. 2008 Jun;82(6):453-63
pubmed: 18435457
Diab Vasc Dis Res. 2007 Jun;4(2):143-50
pubmed: 17654449
J Thromb Haemost. 2013 Jun;11(6):1103-10
pubmed: 23551875
Stroke. 2004 Jun;35(6):1299-304
pubmed: 15131313
J Appl Toxicol. 2009 May;29(4):364-6
pubmed: 19058293