USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage

Shohei Takahashi, Daisuke Fukuhara, Toru Kimura, Toshiyuki Fukutomi, Eriko Tanaka, Naoaki Mikami, Ichiro Hada, Hiromu Takematsu, Yukino Nishibori, Yoshihiro Akimoto, Hiroshi Kiyonari, Takaya Abe, Otmar Huber, Kunimasa Yan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)198-206
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume614
DOIs
Publication statusPublished - 23-07-2022

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage'. Together they form a unique fingerprint.

Cite this