The AMPK-Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
19
07
2018
accepted:
05
06
2019
pubmed:
31
7
2019
medline:
20
11
2019
entrez:
31
7
2019
Statut:
ppublish
Résumé
The receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 play important roles in necroptosis that are closely linked to the inflammatory response. Although the activation of necroptosis is well characterized, the mechanism that tunes down necroptosis is largely unknown. Here we find that Parkin (also known as PARK2), an E3 ubiquitin ligase implicated in Parkinson's disease and as a tumour suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation and necroptosis. Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis by inhibiting RIPK1-RIPK3 complex formation; this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.
Identifiants
pubmed: 31358971
doi: 10.1038/s41556-019-0356-8
pii: 10.1038/s41556-019-0356-8
pmc: PMC6679774
mid: NIHMS1531202
doi:
Substances chimiques
Ubiquitin-Protein Ligases
EC 2.3.2.27
parkin protein
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
940-951Subventions
Organisme : NCI NIH HHS
ID : R01 CA203561
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA224921
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS085070
Pays : United States
Commentaires et corrections
Type : CommentIn
Références
J Biol Chem. 2013 Jul 26;288(30):22019-32
pubmed: 23754282
J Neurochem. 2008 Jun;105(5):1806-19
pubmed: 18248624
J Cell Biol. 2014 Apr 28;205(2):143-53
pubmed: 24751536
Eur J Biochem. 1989 Dec 8;186(1-2):123-8
pubmed: 2574667
J Biol Chem. 2015 May 1;290(18):11635-48
pubmed: 25778401
Nature. 2016 Apr 14;532(7598):245-9
pubmed: 27049944
Mol Cancer. 2015 Feb 21;14:48
pubmed: 25743109
Mol Biol Cell. 2002 Mar;13(3):978-88
pubmed: 11907276
Cell Death Differ. 2014 Nov;21(11):1709-20
pubmed: 24902902
Gut. 2008 Oct;57(10):1398-405
pubmed: 18523026
Cancer Sci. 2003 Nov;94(11):965-73
pubmed: 14611673
J Biol Chem. 2005 Feb 4;280(5):3390-9
pubmed: 15557340
Biochem Pharmacol. 2015 Mar 1;94(1):1-11
pubmed: 25562745
Sci Rep. 2017 Jul 19;7(1):5818
pubmed: 28724891
Mol Cell. 2014 Nov 20;56(4):481-95
pubmed: 25459880
Oncotarget. 2016 Jul 12;7(28):44211-44223
pubmed: 27329585
Mol Cell. 2016 Feb 18;61(4):614-624
pubmed: 26876938
Nature. 2014 Jun 5;510(7503):162-6
pubmed: 24784582
Mol Cell. 2008 Apr 25;30(2):214-26
pubmed: 18439900
Nature. 2015 Jan 15;517(7534):311-20
pubmed: 25592536
Nature. 2009 Apr 23;458(7241):1056-60
pubmed: 19262508
Nat Protoc. 2007;2(8):1998-2004
pubmed: 17703211
J Biol Chem. 2010 Dec 3;285(49):38214-23
pubmed: 20889974
Semin Cell Dev Biol. 2015 Mar;39:63-9
pubmed: 25736836
Cell. 2012 Jul 20;150(2):339-50
pubmed: 22817896
Cancer Res. 1997 May 15;57(10):1835-40
pubmed: 9157970
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15145-50
pubmed: 20696900
Nat Genet. 2010 Jan;42(1):77-82
pubmed: 19946270
Oncogene. 2008 Oct 9;27(46):6002-11
pubmed: 18574468
World J Gastroenterol. 2014 Aug 7;20(29):9872-81
pubmed: 25110418
Cell. 2012 Jan 20;148(1-2):213-27
pubmed: 22265413
Cell. 2009 Jun 12;137(6):1112-23
pubmed: 19524513
PLoS Pathog. 2015 Dec 11;11(12):e1005337
pubmed: 26659062
Mol Cell. 2015 Oct 1;60(1):21-34
pubmed: 26387737
Cell Death Differ. 1997 Aug;4(6):429-34
pubmed: 16465263
Biochem Soc Trans. 2003 Feb;31(Pt 1):162-8
pubmed: 12546677
Semin Immunopathol. 2013 Mar;35(2):229-44
pubmed: 23161445
Nature. 2011 Jul 31;477(7364):330-4
pubmed: 21804564
Hum Mol Genet. 2009 Oct 15;18(20):3832-50
pubmed: 19617636
Oncogene. 2012 Dec 6;31(49):5045-60
pubmed: 22310284
Front Immunol. 2012 May 08;3:107
pubmed: 22586430
Biochim Biophys Acta. 2013 Dec;1833(12):3448-3459
pubmed: 23770045
Nat Genet. 2000 Jul;25(3):302-5
pubmed: 10888878
Clin Cancer Res. 2004 Apr 15;10(8):2720-4
pubmed: 15102676