USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage.
Biochem Biophys Res Commun
; 614: 198-206, 2022 07 23.
Article
de En
| MEDLINE
| ID: mdl-35605301
ABSTRACT
Podocyte damage is a major pathological lesion leading to focal segmental glomerulosclerosis (FSGS). Podocytes damaged by cellular stress undergo hypertrophy to compensate for podocytopenia. It is known that cyclin-dependent kinase inhibitors induced by p53 ensure podocytes hypertrophy; however, its precise mechanism remains to be further investigated. In this study, we found that ubiquitin specific protease 40 (USP40) is a novel regulator of p53. Although USP40 knockout mice established in the present study revealed no abnormal kidney phenotype, intermediate filament Nestin was upregulated in the glomeruli, and was bound to and colocalized with USP40. We also found that USP40 deubiquitinated histidine triad nucleotide-binding protein 1 (HINT1), an inducer of p53. Gene knockdown experiments of USP40 in cultured podocytes revealed the reduction of HINT1 and p53 protein expression. Finally, in glomerular podocytes of mouse FSGS, upregulation of HINT1 occurred in advance of the proteinuria, which was followed by upregulation of USP40, p53 and Nestin. In conclusion, USP40 bound to Nestin deubiquitinates HINT1, and in consequence upregulates p53. These results provide additional insight into the pathological mechanism of podocyte hypertrophy in FSGS.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Glomérulonéphrite segmentaire et focale
/
Protéine p53 suppresseur de tumeur
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Podocytes
/
Nestine
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Ubiquitin-specific proteases
/
Protéines de tissu nerveux
Limites:
Animals
Langue:
En
Journal:
Biochem Biophys Res Commun
Année:
2022
Type de document:
Article
Pays d'affiliation:
Japon