Loss of PIKfyve drives the spongiform degeneration in prion diseases.
neurodegeneration
palmitoylation
prion
spongiosis
unfolded protein response
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 09 2021
07 09 2021
Historique:
revised:
23
06
2021
received:
15
06
2021
accepted:
25
06
2021
pubmed:
23
7
2021
medline:
26
10
2021
entrez:
22
7
2021
Statut:
ppublish
Résumé
Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion-mimetic antibodies deplete the phosphoinositide kinase PIKfyve-which controls endolysosomal maturation-from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB-dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P
Identifiants
pubmed: 34291577
doi: 10.15252/emmm.202114714
pmc: PMC8518562
doi:
Substances chimiques
Acyltransferases
EC 2.3.-
Zdhhc21 protein, mouse
EC 2.3.1.-
Pikfyve protein, mouse
EC 2.7.1.137
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14714Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Brain Res. 1993 Feb 19;603(2):343-7
pubmed: 8461987
Nat Rev Mol Cell Biol. 2007 Jan;8(1):74-84
pubmed: 17183362
Nat Cell Biol. 2015 Mar;17(3):288-99
pubmed: 25720963
F1000Res. 2015 Jul 16;4:261
pubmed: 26339475
J Neurosci. 2015 Sep 2;35(35):12137-51
pubmed: 26338325
EMBO Mol Med. 2021 Sep 7;13(9):e14714
pubmed: 34291577
PLoS Pathog. 2015 Feb 24;11(2):e1004662
pubmed: 25710374
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17518-23
pubmed: 17956977
Mol Biol Cell. 2012 Jan;23(1):188-99
pubmed: 22031296
Annu Rev Pathol. 2008;3:11-40
pubmed: 18233951
Oxid Med Cell Longev. 2015;2015:238914
pubmed: 26301039
J Inherit Metab Dis. 2015 Jan;38(1):179-86
pubmed: 25091425
PLoS Pathog. 2012;8(11):e1002985
pubmed: 23133383
Science. 2009 Jul 24;325(5939):473-7
pubmed: 19556463
Nature. 1996 Jan 25;379(6563):339-43
pubmed: 8552188
Cell Chem Biol. 2018 Mar 15;25(3):236-246
pubmed: 29290622
Int J Alzheimers Dis. 2012;2012:752894
pubmed: 22970406
J Pathol. 1992 Apr;166(4):333-41
pubmed: 1355530
Br Med Bull. 2003;66:213-39
pubmed: 14522861
PLoS Pathog. 2020 Jun 29;16(6):e1008653
pubmed: 32598380
Prion. 2013 Jul-Aug;7(4):267-71
pubmed: 23787699
Cell. 2018 Aug 9;174(4):999-1014.e22
pubmed: 30096314
J Cell Sci. 2013 Sep 1;126(Pt 17):3893-903
pubmed: 23843619
Nat Protoc. 2008;3(4):555-62
pubmed: 18388937
Nature. 2013 Sep 5;501(7465):102-6
pubmed: 23903654
FEBS J. 2019 Jan;286(2):342-355
pubmed: 29476642
J Biol Chem. 2012 Jun 1;287(23):18872-87
pubmed: 22493452
Nature. 2012 May 06;485(7399):507-11
pubmed: 22622579
Nat Methods. 2007 Dec;4(12):1023-30
pubmed: 18026110
Neuropathology. 2017 Apr;37(2):174-188
pubmed: 28028861
J Biol Chem. 2017 May 19;292(20):8424-8435
pubmed: 28360104
Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3466-75
pubmed: 26100893
J Cell Sci. 2005 Jul 15;118(Pt 14):3003-17
pubmed: 16014378
Prion. 2019 Jan;13(1):83-93
pubmed: 30966865
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17472-7
pubmed: 23047693
Nature. 2007 Jul 5;448(7149):68-72
pubmed: 17572665
Neuron. 1990 Jul;5(1):1-10
pubmed: 2196069
Prog Neurobiol. 2012 May;97(2):220-38
pubmed: 22155432
Acta Neuropathol. 2019 Dec;138(6):943-970
pubmed: 31456031
J Virol. 2007 Mar;81(6):2831-7
pubmed: 17182694
Nat Rev Neurosci. 2010 Mar;11(3):161-75
pubmed: 20168314
J Exp Med. 2016 Mar 7;213(3):313-27
pubmed: 26926995
PLoS One. 2012;7(3):e33889
pubmed: 22470488
Pharmacol Res. 2016 Sep;111:133-151
pubmed: 27293050
Bioessays. 2014 Jan;36(1):52-64
pubmed: 24323921
Sci Rep. 2016 Feb 11;6:21658
pubmed: 26865414
Sci Transl Med. 2013 Oct 9;5(206):206ra138
pubmed: 24107777
EMBO J. 1996 Mar 15;15(6):1255-64
pubmed: 8635458
Science. 2003 Jan 31;299(5607):710-2
pubmed: 12560552
Cell. 1993 Jul 2;73(7):1339-47
pubmed: 8100741
J Cell Sci. 2018 May 21;131(10):
pubmed: 29661845
J Biol Chem. 2009 Dec 18;284(51):35794-806
pubmed: 19840946
J Biochem. 2019 Jan 1;165(1):75-84
pubmed: 30295876
J Biol Chem. 2017 Feb 24;292(8):3445-3455
pubmed: 28087698
J Exp Med. 2019 Apr 1;216(4):743-756
pubmed: 30842236
Cell Calcium. 2018 Jan;69:112-121
pubmed: 28689729
Sci Transl Med. 2015 Aug 5;7(299):299ra123
pubmed: 26246168
PLoS One. 2013;8(1):e55575
pubmed: 23383230
Ann N Y Acad Sci. 2003 Jun;994:288-98
pubmed: 12851328
Cell. 2009 Jun 12;137(6):1136-47
pubmed: 19524515
Nat Commun. 2014 Sep 02;5:4691
pubmed: 25178411
J Biol Chem. 2021 Jan-Jun;296:100636
pubmed: 33831417