The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 10 2023
05 10 2023
Historique:
received:
11
03
2021
accepted:
20
09
2023
medline:
23
10
2023
pubmed:
6
10
2023
entrez:
5
10
2023
Statut:
epublish
Résumé
The relative abundance of Wnt receptors plays a crucial role in controlling Wnt signaling in tissue homeostasis and human disease. While the ubiquitin ligases that ubiquitylate Wnt receptors are well-characterized, the deubiquitylase that reverses these reactions remains unclear. Herein, we identify USP46, UAF1, and WDR20 (USP46 complex) as positive regulators of Wnt signaling in cultured human cells. We find that the USP46 complex is similarly required for Wnt signaling in Xenopus and zebrafish embryos. We demonstrate that Wnt signaling promotes the association between the USP46 complex and cell surface Wnt coreceptor, LRP6. Knockdown of USP46 decreases steady-state levels of LRP6 and increases the level of ubiquitylated LRP6. In contrast, overexpression of the USP46 complex blocks ubiquitylation of LRP6 by the ubiquitin ligases RNF43 and ZNFR3. Size exclusion chromatography studies suggest that the size of the USP46 cytoplasmic complex increases upon Wnt stimulation. Finally, we show that USP46 is essential for Wnt-dependent intestinal organoid viability, likely via its role in LRP6 receptor homeostasis. We propose a model in which the USP46 complex increases the steady-state level of cell surface LRP6 and facilitates the assembly of LRP6 into signalosomes via a pruning mechanism that removes sterically hindering ubiquitin chains.
Identifiants
pubmed: 37798301
doi: 10.1038/s41467-023-41836-z
pii: 10.1038/s41467-023-41836-z
pmc: PMC10556042
doi:
Substances chimiques
beta Catenin
0
Ligases
EC 6.-
Low Density Lipoprotein Receptor-Related Protein-6
0
LRP6 protein, human
0
Receptors, Wnt
0
Ubiquitin
0
ubiquitin-specific peptidase 46, human
EC 3.4.-
Endopeptidases
EC 3.4.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6173Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM113132
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA281002
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023108
Pays : United States
Organisme : Cancer Research UK
ID : A28592
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R35 GM136233
Pays : United States
Organisme : NIH HHS
ID : S10 OD032310
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244188
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
Références
Cell. 1989 Sep 22;58(6):1075-84
pubmed: 2673541
Nat Rev Drug Discov. 2004 Jun;3(6):479-87
pubmed: 15173837
Methods Cell Biol. 1991;36:657-62
pubmed: 1811156
Mol Cell. 2016 Jul 21;63(2):249-260
pubmed: 27373336
EMBO J. 2010 Jul 7;29(13):2114-25
pubmed: 20495530
Proc Natl Acad Sci U S A. 1999 May 25;96(11):6273-8
pubmed: 10339577
Nat Genet. 2013 Oct;45(10):1113-20
pubmed: 24071849
Genes Dev. 2019 Feb 1;33(3-4):209-220
pubmed: 30692207
Elife. 2016 Oct 18;5:
pubmed: 27751231
Proc Natl Acad Sci U S A. 2016 May 24;113(21):E2945-54
pubmed: 27162353
Dev Cell. 2018 Mar 12;44(5):566-581.e8
pubmed: 29533772
Nature. 2012 Aug 30;488(7413):665-9
pubmed: 22895187
Cell Discov. 2019 Jul 2;5:34
pubmed: 31632687
Nature. 2012 Aug 30;488(7413):660-4
pubmed: 22895193
Nucleic Acids Res. 2017 Jul 3;45(W1):W98-W102
pubmed: 28407145
Trends Cell Biol. 2020 Jan;30(1):60-73
pubmed: 31718893
Diabetes. 2003 Mar;52(3):588-95
pubmed: 12606497
Nature. 2009 May 14;459(7244):262-5
pubmed: 19329995
J Neurochem. 2015 Sep;134(6):1067-80
pubmed: 26077708
Mech Dev. 2019 Apr;156:20-31
pubmed: 30904594
Front Cell Neurosci. 2017 Oct 13;11:318
pubmed: 29081735
Mol Cell. 2018 Dec 6;72(5):823-835.e5
pubmed: 30415951
Development. 2006 Apr;133(7):1205-17
pubmed: 16527985
J Biol Chem. 2010 Apr 9;285(15):11252-7
pubmed: 20147737
Nature. 2012 Apr 29;485(7397):195-200
pubmed: 22575959
Diabetes. 2002 Oct;51(10):2903-10
pubmed: 12351425
Nature. 2009 Oct 1;461(7264):614-20
pubmed: 19759537
J Biol Chem. 2014 Feb 7;289(6):3444-56
pubmed: 24356955
Nat Commun. 2015 Apr 24;6:6718
pubmed: 25907794
Neoplasia. 2017 Aug;19(8):649-658
pubmed: 28732212
Growth Factors. 2013 Feb;31(1):1-31
pubmed: 23256519
Mol Cell. 2012 Mar 9;45(5):619-28
pubmed: 22304967
J Biol Chem. 2020 Aug 14;295(33):11776-11788
pubmed: 32587090
Development. 2004 Jun;131(12):2899-909
pubmed: 15151990
Cell. 2002 Mar 22;108(6):837-47
pubmed: 11955436
Structure. 2015 Nov 3;23(11):2043-54
pubmed: 26388029
Cell. 2004 Mar 19;116(6):883-95
pubmed: 15035989
Cell Syst. 2018 Jan 24;6(1):52-64.e4
pubmed: 29199019
Cell. 2012 Jun 8;149(6):1192-205
pubmed: 22682243
Chem Biol. 2011 Dec 23;18(12):1550-61
pubmed: 22195557
Nat Commun. 2023 Oct 5;14(1):6174
pubmed: 37798281
EMBO Rep. 2021 May 5;22(5):e51415
pubmed: 33786993
Nature. 2011 Jan 20;469(7330):415-8
pubmed: 21113151
Sci Signal. 2017 Jun 27;10(485):
pubmed: 28655862
Nat Genet. 2014 Dec;46(12):1264-6
pubmed: 25344691
Elife. 2016 Dec 20;5:
pubmed: 27996937
Cell. 1991 Nov 15;67(4):741-52
pubmed: 1834344
Science. 2007 Jun 15;316(5831):1619-22
pubmed: 17569865
Mol Cell. 2015 May 7;58(3):522-33
pubmed: 25891077
Cold Spring Harb Perspect Biol. 2012 Dec 01;4(12):
pubmed: 23209147
Front Synaptic Neurosci. 2017 Dec 14;9:16
pubmed: 29302259