Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
04 10 2023
04 10 2023
Historique:
received:
13
05
2023
revised:
25
07
2023
accepted:
26
07
2023
pmc-release:
31
07
2024
medline:
5
10
2023
pubmed:
31
7
2023
entrez:
31
7
2023
Statut:
ppublish
Résumé
Aggregation of TAR DNA-binding protein 43 kDa (TDP-43) is thought to drive the pathophysiology of amyotrophic lateral sclerosis and some frontotemporal dementias. TDP-43 is normally a nuclear protein that in neurons translocates to the cytoplasm and can form insoluble aggregates upon activation of the integrated stress response (ISR). Viruses evolved to control the ISR. In the case of Herpesvirus 8, the protein ORF57 acts to bind protein kinase R, inhibit phosphorylation of eIF2α and reduce activation of the ISR. We hypothesized that ORF57 might also possess the ability to inhibit aggregation of TDP-43. ORF57 was expressed in the neuronal SH-SY5Y line and its effects on TDP-43 aggregation characterized. We report that ORF57 inhibits TDP-43 aggregation by 55% and elicits a 2.45-fold increase in the rate of dispersion of existing TDP-43 granules. These changes were associated with a 50% decrease in cell death. Proteomic studies were carried out to identify the protein interaction network of ORF57. We observed that ORF57 directly binds to TDP-43 as well as interacts with many components of the ISR, including elements of the proteostasis machinery known to reduce TDP-43 aggregation. We propose that viral proteins designed to inhibit a chronic ISR can be engineered to remove aggregated proteins and dampen a chronic ISR.
Identifiants
pubmed: 37522762
pii: 7234031
doi: 10.1093/hmg/ddad122
pmc: PMC10549787
doi:
Substances chimiques
DNA-Binding Proteins
0
ORF57 protein, human herpesvirus 8
0
Viral Regulatory and Accessory Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2966-2980Subventions
Organisme : NIBIB NIH HHS
ID : R01 EB029483
Pays : United States
Organisme : NIH HHS
ID : AG080810
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Acta Neuropathol. 2015 Nov;130(5):643-60
pubmed: 26197969
J Biol Chem. 2006 Sep 22;281(38):28365-78
pubmed: 16829516
Mol Cell Biol. 1995 Aug;15(8):4497-506
pubmed: 7623840
Science. 2021 Feb 5;371(6529):
pubmed: 33335017
J Proteome Res. 2023 Feb 3;22(2):374-386
pubmed: 36541440
PLoS One. 2010 Oct 11;5(10):e13250
pubmed: 20948999
Cell. 2014 Jan 16;156(1-2):170-82
pubmed: 24439375
J Cell Physiol. 2013 Nov;228(11):2222-31
pubmed: 23625794
ACS Chem Biol. 2015 Dec 18;10(12):2672-9
pubmed: 26441009
Nucleic Acids Res. 2022 Jan 7;50(D1):D543-D552
pubmed: 34723319
Philos Trans R Soc Lond B Biol Sci. 2018 Jan 19;373(1738):
pubmed: 29203718
Cell Syst. 2020 Aug 26;11(2):208
pubmed: 32853540
Cell. 2018 Apr 19;173(3):677-692.e20
pubmed: 29677512
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):20881-90
pubmed: 22065782
J Clin Invest. 2020 Nov 2;130(11):6080-6092
pubmed: 32790644
Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15420-5
pubmed: 26627716
Am J Pathol. 2008 Jul;173(1):182-94
pubmed: 18535185
Neurobiol Dis. 2020 Mar;136:104702
pubmed: 31837419
PLoS Genet. 2021 Nov 1;17(11):e1009882
pubmed: 34723963
Sci Adv. 2020 May 06;6(19):eaay8828
pubmed: 32494701
J Cell Biol. 2013 Apr 29;201(3):361-72
pubmed: 23629963
J Virol. 2006 Jun;80(11):5251-60
pubmed: 16699005
J Biol Chem. 2005 Apr 29;280(17):16925-33
pubmed: 15684421
Nat Neurosci. 2014 May;17(5):664-666
pubmed: 24686783
Elife. 2020 Dec 15;9:
pubmed: 33319748
PLoS Pathog. 2018 Aug 10;14(8):e1007232
pubmed: 30096191
Science. 2009 Feb 27;323(5918):1208-1211
pubmed: 19251628
Nucleic Acids Res. 2019 Sep 26;47(17):9368-9385
pubmed: 31400113
Nat Neurosci. 2019 Feb;22(2):180-190
pubmed: 30643298
Neurobiol Dis. 2019 Dec;132:104514
pubmed: 31229690
Neurosci Lett. 2007 Dec 18;429(2-3):95-100
pubmed: 17980964
Nucleic Acids Res. 2017 Jan 4;45(D1):D1100-D1106
pubmed: 27924013
Neuron. 2019 Apr 17;102(2):321-338.e8
pubmed: 30826182
Mol Biol Rep. 2022 Aug;49(8):7623-7635
pubmed: 35612780
Nature. 2022 Mar;603(7899):124-130
pubmed: 35197626
Nucleic Acids Res. 2018 Jul 2;46(W1):W467-W472
pubmed: 29901776
J Biol Chem. 2020 Dec 18;295(51):17672-17683
pubmed: 33454006
J Virol. 2022 Feb 9;96(3):e0178221
pubmed: 34787459
FEBS J. 2019 Jan;286(2):342-355
pubmed: 29476642
J Clin Invest. 2018 Mar 1;128(3):1164-1177
pubmed: 29457785
Mol Neurodegener. 2017 Feb 2;12(1):13
pubmed: 28153034
FEBS Lett. 2022 Jun;596(11):1412-1423
pubmed: 35445401
Neuron. 2013 Apr 10;78(1):65-80
pubmed: 23498974
Hum Mol Genet. 2015 Sep 15;24(18):5154-73
pubmed: 26130692
Nat Genet. 2014 Feb;46(2):152-60
pubmed: 24336168
Mol Cell. 2021 Oct 21;81(20):4209-4227.e12
pubmed: 34453888
Neuron. 2019 Apr 17;102(2):339-357.e7
pubmed: 30853299
Front Neurol. 2018 Mar 19;9:147
pubmed: 29599744
J Neuroinflammation. 2020 Dec 7;17(1):371
pubmed: 33287823
Autophagy. 2023 Jun;19(6):1619-1641
pubmed: 36594740
Nature. 2022 Mar;603(7899):131-137
pubmed: 35197628
J Alzheimers Dis. 2009;16(2):341-50
pubmed: 19221424
J Biol Chem. 1998 Jan 23;273(4):2416-23
pubmed: 9442091
Science. 2009 Feb 27;323(5918):1205-8
pubmed: 19251627
J Virol. 2013 Jan;87(1):243-56
pubmed: 23077296
Nat Rev Neurosci. 2019 Nov;20(11):649-666
pubmed: 31582840
Nat Cell Biol. 2008 Nov;10(11):1324-32
pubmed: 18836437
J Biol Chem. 2009 May 1;284(18):12384-98
pubmed: 19237541
Neuron. 2019 Apr 17;102(2):265-267
pubmed: 30998893
Arch Neurol. 2011 Nov;68(11):1440-6
pubmed: 22084127
Bioinformatics. 2020 Apr 15;36(8):2628-2629
pubmed: 31882993
J Biol Chem. 2007 Aug 17;282(33):24131-45
pubmed: 17580304
Cell Death Differ. 2014 Dec;21(12):1838-51
pubmed: 25034784
Science. 2015 Aug 7;349(6248):650-5
pubmed: 26250685
Neuron. 2018 Jul 11;99(1):56-63.e3
pubmed: 30001512
Acta Neuropathol. 2014 Sep;128(3):397-410
pubmed: 24899140
PLoS Pathog. 2017 Oct 30;13(10):e1006677
pubmed: 29084250
J Virol. 2000 Apr;74(8):3586-97
pubmed: 10729134
J Virol. 2008 Mar;82(6):2792-801
pubmed: 18184716
Curr Opin Genet Dev. 2017 Jun;44:1-8
pubmed: 28208059
Eur J Neurosci. 2008 Nov;28(10):2003-16
pubmed: 19046382
Cold Spring Harb Perspect Med. 2018 May 01;8(5):
pubmed: 28270533
Front Aging Neurosci. 2021 Mar 26;13:658226
pubmed: 33841129
Nat Neurosci. 2018 Feb;21(2):228-239
pubmed: 29311743
CNS Neurosci Ther. 2022 Jan;28(1):105-115
pubmed: 34750982
Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18591-18599
pubmed: 32690681
Bioinformatics. 2012 Jul 1;28(13):1800-1
pubmed: 22543368
Nat Methods. 2009 Apr;6(4):275-7
pubmed: 19305406
Alzheimers Dement. 2023 Jul;19(7):2805-2815
pubmed: 36576960
Brain Pathol. 2022 Jul;32(4):e13044
pubmed: 34913212
Mol Cell. 2000 May;5(5):897-904
pubmed: 10882126
Science. 2006 Oct 6;314(5796):130-3
pubmed: 17023659
Science. 1994 Dec 16;266(5192):1865-9
pubmed: 7997879