Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis.
Actinin
/ genetics
Actins
/ metabolism
Albuminuria
/ etiology
Animals
Cells, Cultured
Female
Glomerulosclerosis, Focal Segmental
/ etiology
Glucose
/ pharmacology
Humans
Lab-On-A-Chip Devices
Male
Mice
Nephrectomy
/ adverse effects
Peptidomimetics
Phosphorylation
/ drug effects
Podocytes
/ metabolism
Protein Binding
Protein Processing, Post-Translational
Serine
/ metabolism
Transforming Growth Factor beta
/ pharmacology
chronic kidney disease
cytoskeleton
focal segmental glomerulosclerosis
glomerular disease
podocyte
proteinuria
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
09
10
2019
accepted:
23
03
2020
pubmed:
17
6
2020
medline:
25
2
2021
entrez:
17
6
2020
Statut:
ppublish
Résumé
Genetic mutations in Using mass spectrometry, we found that ACTN4 is phosphorylated at serine (S) 159 in human podocytes. We used phosphomimetic and nonphosphorylatable ACTN4 to comprehensively study the effects of this phosphorylation Compared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin These findings suggest that increased phosphorylation of ACTN4 at S159 leads to biochemical, cellular, and renal pathology that is similar to pathology resulting from human disease-causing mutations in ACTN4. ACTN4 may mediate podocyte injury as a consequence of both genetic mutations and signaling events that modulate phosphorylation.
Sections du résumé
BACKGROUND
Genetic mutations in
METHODS
Using mass spectrometry, we found that ACTN4 is phosphorylated at serine (S) 159 in human podocytes. We used phosphomimetic and nonphosphorylatable ACTN4 to comprehensively study the effects of this phosphorylation
RESULTS
Compared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin
CONCLUSIONS
These findings suggest that increased phosphorylation of ACTN4 at S159 leads to biochemical, cellular, and renal pathology that is similar to pathology resulting from human disease-causing mutations in ACTN4. ACTN4 may mediate podocyte injury as a consequence of both genetic mutations and signaling events that modulate phosphorylation.
Identifiants
pubmed: 32540856
pii: ASN.2019101032
doi: 10.1681/ASN.2019101032
pmc: PMC7351002
doi:
Substances chimiques
ACTN4 protein, human
0
Actins
0
Actn4 protein, mouse
0
Peptidomimetics
0
Transforming Growth Factor beta
0
Actinin
11003-00-2
Serine
452VLY9402
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1479-1495Subventions
Organisme : NIDDK NIH HHS
ID : K01 DK114329
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034854
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK059588
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007199
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK096493
Pays : United States
Informations de copyright
Copyright © 2020 by the American Society of Nephrology.
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