CMIP interacts with WT1 and targets it on the proteasome degradation pathway.
Acetylcysteine
/ analogs & derivatives
Adaptor Proteins, Signal Transducing
/ antagonists & inhibitors
Animals
Down-Regulation
/ drug effects
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B
/ metabolism
Nephrotic Syndrome
/ metabolism
Podocytes
/ cytology
Proteasome Endopeptidase Complex
/ chemistry
Protein Binding
Proteinuria
/ pathology
RNA Interference
RNA, Small Interfering
/ administration & dosage
Transcriptional Activation
WT1 Proteins
/ genetics
CMIP
WT1
gene therapy
nephrotic syndrome
podocyte
Journal
Clinical and translational medicine
ISSN: 2001-1326
Titre abrégé: Clin Transl Med
Pays: United States
ID NLM: 101597971
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
29
04
2021
received:
06
01
2021
accepted:
25
05
2021
entrez:
29
7
2021
pubmed:
30
7
2021
medline:
1
2
2022
Statut:
ppublish
Résumé
The Wilms tumor 1 suppressor gene, WT1, is expressed throughout life in podocytes and is essential for their function. Downregulation of WT1 has been reported in podocyte diseases but the underlying mechanisms remain unclear. Podocyte injury is the hallmark of idiopathic nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults. An increase in the abundance of Cmaf-inducing protein (CMIP) has been found to alter podocyte function, but it is not known whether CMIP affects WT1 expression. Transcriptional and post-transcriptional regulation of WT1in the presence of CMIP was studied using transient transfection, mouse models, and siRNA handling. We showed that overproduction of CMIP in the podocyte was consistently associated with a downregulation of WT1 according to two mechanisms. We found that CMIP prevented the NF-kB-mediated transcriptional activation of WT1. We demonstrated that CMIP interacts directly with WT1 through its leucine-rich repeat domain. Overexpression of CMIP in the M15 cell line induced a downregulation of WT1, which was prevented by lactacystin, a potent proteasome inhibitor. We showed that CMIP exhibits an E3 ligase activity and targets WT1 to proteasome degradation. Intravenous injection of Cmip-siRNA specifically prevented the repression of Wt1 in lipopolysaccharides-induced proteinuria in mice. These data suggest that CMIP is a repressor of WT1 and might be a critical player in the pathophysiology of some podocyte diseases. Because WT1 is required for podocyte integrity, CMIP could be considered a therapeutic target in podocyte diseases.
Sections du résumé
BACKGROUND
The Wilms tumor 1 suppressor gene, WT1, is expressed throughout life in podocytes and is essential for their function. Downregulation of WT1 has been reported in podocyte diseases but the underlying mechanisms remain unclear. Podocyte injury is the hallmark of idiopathic nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults. An increase in the abundance of Cmaf-inducing protein (CMIP) has been found to alter podocyte function, but it is not known whether CMIP affects WT1 expression.
METHODS
Transcriptional and post-transcriptional regulation of WT1in the presence of CMIP was studied using transient transfection, mouse models, and siRNA handling.
RESULTS
We showed that overproduction of CMIP in the podocyte was consistently associated with a downregulation of WT1 according to two mechanisms. We found that CMIP prevented the NF-kB-mediated transcriptional activation of WT1. We demonstrated that CMIP interacts directly with WT1 through its leucine-rich repeat domain. Overexpression of CMIP in the M15 cell line induced a downregulation of WT1, which was prevented by lactacystin, a potent proteasome inhibitor. We showed that CMIP exhibits an E3 ligase activity and targets WT1 to proteasome degradation. Intravenous injection of Cmip-siRNA specifically prevented the repression of Wt1 in lipopolysaccharides-induced proteinuria in mice.
CONCLUSIONS
These data suggest that CMIP is a repressor of WT1 and might be a critical player in the pathophysiology of some podocyte diseases. Because WT1 is required for podocyte integrity, CMIP could be considered a therapeutic target in podocyte diseases.
Identifiants
pubmed: 34323419
doi: 10.1002/ctm2.460
pmc: PMC8299046
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CMIP protein, human
0
NF-kappa B
0
RNA, Small Interfering
0
WT1 Proteins
0
lactacystin
133343-34-7
Proteasome Endopeptidase Complex
EC 3.4.25.1
Acetylcysteine
WYQ7N0BPYC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e460Informations de copyright
© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
Références
Cell Growth Differ. 1992 May;3(5):279-89
pubmed: 1378753
Mol Immunol. 2009 Feb;46(5):991-8
pubmed: 19019440
J Clin Endocrinol Metab. 2009 Nov;94(11):4334-41
pubmed: 19789204
Nat Commun. 2014 Jul 17;5:4444
pubmed: 25031030
FEBS Lett. 2010 Feb 5;584(3):500-6
pubmed: 20018188
Nucleic Acids Res. 2008 Jul;36(12):4067-78
pubmed: 18535006
Nat Rev Genet. 2003 Dec;4(12):948-58
pubmed: 14631355
Am J Nephrol. 2009;29(6):558-70
pubmed: 19136817
J Am Soc Nephrol. 2011 Jan;22(1):90-103
pubmed: 21030600
Biochem Pharmacol. 2019 Aug;166:139-152
pubmed: 31085161
Development. 2017 Aug 15;144(16):2862-2872
pubmed: 28811308
Kidney Int. 2016 Dec;90(6):1298-1311
pubmed: 27650733
Cell. 2006 Nov 17;127(4):775-88
pubmed: 17110336
Clin Immunol. 2011 Jun;139(3):314-20
pubmed: 21450528
J Biol Chem. 1992 Nov 5;267(31):21999-2002
pubmed: 1429549
Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5100-4
pubmed: 8389468
J Am Soc Nephrol. 2011 Jul;22(7):1275-85
pubmed: 21719786
Mod Pathol. 2006 Jun;19(6):804-14
pubmed: 16547468
Kidney Int. 2014 Feb;85(2):457-70
pubmed: 24067439
Cell. 1995 May 5;81(3):391-401
pubmed: 7736591
Oncogene. 1998 Apr 23;16(16):2033-9
pubmed: 9572484
Oncogene. 1997 Jun 5;14(22):2689-700
pubmed: 9178767
Mol Cell Biol. 1996 Dec;16(12):6945-56
pubmed: 8943350
Mol Endocrinol. 1994 May;8(5):595-602
pubmed: 8058069
Biomed Res Int. 2017;2017:9531074
pubmed: 28299339
Cell Physiol Biochem. 2015;36(4):1274-90
pubmed: 26160339
Am J Physiol Renal Physiol. 2002 Mar;282(3):F431-41
pubmed: 11832423
J Am Soc Nephrol. 2004 Dec;15(12):3044-51
pubmed: 15579507
EMBO J. 1995 Oct 2;14(19):4662-75
pubmed: 7588596
Sci Signal. 2010 May 18;3(122):ra39
pubmed: 20484117
J Am Soc Nephrol. 2003 May;14(5):1200-11
pubmed: 12707390
Genes Dev. 1998 Oct 15;12(20):3217-25
pubmed: 9784496
Curr Opin Genet Dev. 2005 Oct;15(5):542-7
pubmed: 16099645
J Biol Chem. 2010 Oct 1;285(40):30539-47
pubmed: 20682767
Semin Immunopathol. 2014 Jul;36(4):421-9
pubmed: 24402710
Mol Cell Biol. 1991 Mar;11(3):1707-12
pubmed: 1671709
Essays Biochem. 2005;41:15-30
pubmed: 16250895
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9067-72
pubmed: 8799155
J Biol Chem. 2005 Feb 4;280(5):3817-23
pubmed: 15550400
J Biol Chem. 2010 Jan 22;285(4):2397-414
pubmed: 19920149
PLoS One. 2020 Nov 4;15(11):e0241745
pubmed: 33147279
Curr Biol. 2001 Nov 13;11(22):1805-9
pubmed: 11719225
EMBO J. 1999 Jul 15;18(14):3990-4003
pubmed: 10406804
Am J Pathol. 2012 Jun;180(6):2284-92
pubmed: 22507836
Development. 2015 Apr 1;142(7):1254-66
pubmed: 25804736
Cell. 1992 Nov 27;71(5):777-89
pubmed: 1330326
J Mol Biol. 1976 Jun 14;104(1):243-61
pubmed: 957432
Oncogene. 2010 Feb 18;29(7):1085-92
pubmed: 19966868
J Biol Chem. 1997 Oct 31;272(44):27493-6
pubmed: 9346875
Mol Cell Biol. 1990 Aug;10(8):4243-55
pubmed: 2115122
J Biol Chem. 1999 Dec 17;274(51):36520-6
pubmed: 10593950
Dev Cell. 2011 Sep 13;21(3):559-74
pubmed: 21871842
Hum Mol Genet. 2004 Feb 15;13(4):463-71
pubmed: 14681305
Curr Biol. 2006 Apr 18;16(8):793-800
pubmed: 16631587
J Biol Chem. 1997 May 16;272(20):13437-45
pubmed: 9148969
J Biol Chem. 1998 May 1;273(18):10880-7
pubmed: 9556563