MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake.
MDM2
SARS-CoV-2 uptake
angiotensin-converting enzyme 2 (ACE2)
severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)
ubiquitination
Journal
Viruses
ISSN: 1999-4915
Titre abrégé: Viruses
Pays: Switzerland
ID NLM: 101509722
Informations de publication
Date de publication:
18 08 2023
18 08 2023
Historique:
received:
02
06
2023
revised:
20
07
2023
accepted:
07
08
2023
medline:
28
8
2023
pubmed:
26
8
2023
entrez:
26
8
2023
Statut:
epublish
Résumé
Angiotensin-converting enzyme 2 (ACE2) is the central entry receptor for SARS-CoV-2. However, surprisingly little is known about the effects of host regulators on ACE2 localization, expression, and the associated influence on SARS-CoV-2 infection. Here we identify that ACE2 expression levels are regulated by the E3 ligase MDM2 and that MDM2 levels indirectly influence infection with SARS-CoV-2. Genetic depletion of MDM2 elevated ACE2 expression levels, which strongly promoted infection with all SARS-CoV-2 isolates tested. SARS-CoV-2 spike-pseudotyped viruses and the uptake of non-replication-competent virus-like particles showed that MDM2 affects the viral uptake process. MDM2 ubiquitinates Lysine 788 of ACE2 to induce proteasomal degradation, and degradation of this residue led to higher ACE2 expression levels and superior virus particle uptake. Our study illustrates that cellular regulators of ACE2 stability, such as MDM2, play an important role in defining the infection capabilities of SARS-CoV-2.
Identifiants
pubmed: 37632105
pii: v15081763
doi: 10.3390/v15081763
pmc: PMC10459000
pii:
doi:
Substances chimiques
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Lysine
K3Z4F929H6
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Références
Int J Mol Sci. 2020 Apr 24;21(8):
pubmed: 32344526
J Virol. 2007 Jan;81(2):718-31
pubmed: 17079322
Front Cell Infect Microbiol. 2022 Jun 14;12:838213
pubmed: 35774397
Nat Immunol. 2011 Jun 05;12(7):624-30
pubmed: 21642987
Front Med. 2021 Apr;15(2):252-263
pubmed: 33511555
EMBO J. 2021 Aug 16;40(16):e107821
pubmed: 34159616
Leukemia. 2020 Nov;34(11):2858-2874
pubmed: 32651541
J Biomed Res. 2013 Jul;27(4):254-71
pubmed: 23885265
EMBO J. 2022 Sep 1;41(17):e111608
pubmed: 35833542
EMBO J. 2019 Nov 15;38(22):e101994
pubmed: 31625181
Genome Biol. 2001;2(11):REVIEWS3012
pubmed: 11737951
Sci Rep. 2019 Jul 18;9(1):10471
pubmed: 31320712
PNAS Nexus. 2022 May;1(2):
pubmed: 36382127
JCI Insight. 2016 Oct 20;1(17):e87877
pubmed: 27777973
Science. 2020 Nov 13;370(6518):856-860
pubmed: 33082293
Exp Gerontol. 2017 Dec 1;99:35-45
pubmed: 28918363
Front Med (Lausanne). 2022 Jul 14;9:902713
pubmed: 35911386
Front Pharmacol. 2020 Jul 29;11:1156
pubmed: 32848765
Cell Res. 2021 Feb;31(2):126-140
pubmed: 33420426
EMBO J. 1991 May;10(5):1091-101
pubmed: 2022183
Cell Discov. 2021 May 4;7(1):31
pubmed: 33947832
Nucleic Acids Res. 2015 Jan;43(Database issue):D512-20
pubmed: 25514926
Signal Transduct Target Ther. 2021 Aug 25;6(1):315
pubmed: 34433803
Circulation. 2020 Sep 22;142(12):1190-1204
pubmed: 32755395
Cell. 2020 Aug 20;182(4):812-827.e19
pubmed: 32697968
Signal Transduct Target Ther. 2021 Jun 1;6(1):214
pubmed: 34075025
Signal Transduct Target Ther. 2022 Sep 7;7(1):312
pubmed: 36071039
Endocrinology. 2007 May;148(5):2453-7
pubmed: 17303661
mBio. 2022 Oct 31;13(6):e0230822
pubmed: 36314791
J Virol. 2014 Mar;88(6):3464-73
pubmed: 24403578
J Cell Biol. 2002 Feb 18;156(4):653-64
pubmed: 11839770
J Med Virol. 2023 Jan;95(1):e28116
pubmed: 36056469
Nature. 2020 Aug;584(7821):430-436
pubmed: 32640463
Nature. 2021 Jun;594(7862):246-252
pubmed: 33845483
Hellenic J Cardiol. 2021 Jan-Feb;62(1):13-23
pubmed: 32522617
Viruses. 2022 Jun 27;14(7):
pubmed: 35891385
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Emerg Infect Dis. 2020 Aug;26(8):
pubmed: 32396505
Int J Mol Sci. 2020 May 20;21(10):
pubmed: 32443911
Nat Commun. 2020 Mar 27;11(1):1620
pubmed: 32221306
Nat Rev Mol Cell Biol. 2022 Jan;23(1):3-20
pubmed: 34611326
Mol Med Rep. 2018 Sep;18(3):3271-3279
pubmed: 30066929
J Immunol. 2011 Dec 15;187(12):6428-36
pubmed: 22105999
Infect Dis Poverty. 2020 Apr 28;9(1):45
pubmed: 32345362
J Virol. 2020 Aug 31;94(18):
pubmed: 32641482
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
Front Microbiol. 2022 Mar 09;13:854567
pubmed: 35356515
EMBO Rep. 2022 Jun 7;23(6):e54305
pubmed: 35527514
Viruses. 2010 Jan;2(1):298-313
pubmed: 21994612
Front Microbiol. 2021 Aug 13;12:654709
pubmed: 34484133
Int J Mol Sci. 2020 Aug 07;21(16):
pubmed: 32784555
J Cell Physiol. 2010 Nov;225(2):326-32
pubmed: 20589833
Science. 2020 Dec 18;370(6523):1464-1468
pubmed: 33184236