The ubiquitin E3 ligase CHIP promotes proteasomal degradation of the serine/threonine protein kinase PINK1 during staurosporine-induced cell death

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Mutations in the gene for the serine/threonine protein kinase PTEN-induced putative kinase 1 (PINK1) are the second most frequent cause of autosomal recessive Parkinson’s disease (PD). Via its kinase activity, PINK1 regulates neuronal cell survival and mitochondrial quality control. Numerous reports have revealed that PINK1 has diverse and physiologically significant functions, and therefore its activity should be tightly regulated. However, the molecular mechanisms regulating PINK1 stability and the modulator(s) involved have not been elucidated. In this study, we demonstrate that the ubiquitin E3 ligase carboxyl terminus of Hsp70-interacting protein (CHIP) promotes PINK1 ubiquitination and decreases its steady-state levels. Moreover, PINK1 levels were strongly reduced in HEK293 and SH-SY5Y cells exposed to the apoptosis-inducer staurosporine. Of note, we found that this reduction resulted from CHIP-mediated PINK1 ubiquitination. Accordingly, siRNA-mediated CHIP knockdown reduced susceptibility to staurosporine-induced cell death. Taken together, these findings suggest that CHIP plays a role in negative regulation of PINK1 stability and may suppress PINK1’s cytoprotective effect during staurosporine-induced mammalian cell death. We propose that this PINK1 regulatory pathway might contribute to Parkinson’s disease pathogenesis.

Original languageEnglish
Pages (from-to)1286-1297
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number4
DOIs
Publication statusPublished - 2018 Jan 1

Fingerprint

Ubiquitin-Protein Ligases
Staurosporine
Protein-Serine-Threonine Kinases
Cell death
Cell Death
Degradation
Proteins
Ubiquitination
Parkinson Disease
PTEN-induced putative kinase
Quality Control
Modulators
Small Interfering RNA
Quality control
Cell Survival
Phosphotransferases
Genes
Cells
Apoptosis
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{557069f6df754a4787ac8a6594c23990,
title = "The ubiquitin E3 ligase CHIP promotes proteasomal degradation of the serine/threonine protein kinase PINK1 during staurosporine-induced cell death",
abstract = "Mutations in the gene for the serine/threonine protein kinase PTEN-induced putative kinase 1 (PINK1) are the second most frequent cause of autosomal recessive Parkinson’s disease (PD). Via its kinase activity, PINK1 regulates neuronal cell survival and mitochondrial quality control. Numerous reports have revealed that PINK1 has diverse and physiologically significant functions, and therefore its activity should be tightly regulated. However, the molecular mechanisms regulating PINK1 stability and the modulator(s) involved have not been elucidated. In this study, we demonstrate that the ubiquitin E3 ligase carboxyl terminus of Hsp70-interacting protein (CHIP) promotes PINK1 ubiquitination and decreases its steady-state levels. Moreover, PINK1 levels were strongly reduced in HEK293 and SH-SY5Y cells exposed to the apoptosis-inducer staurosporine. Of note, we found that this reduction resulted from CHIP-mediated PINK1 ubiquitination. Accordingly, siRNA-mediated CHIP knockdown reduced susceptibility to staurosporine-induced cell death. Taken together, these findings suggest that CHIP plays a role in negative regulation of PINK1 stability and may suppress PINK1’s cytoprotective effect during staurosporine-induced mammalian cell death. We propose that this PINK1 regulatory pathway might contribute to Parkinson’s disease pathogenesis.",
author = "Lang Yoo and Chung, {Kwang Chul}",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.M117.803890",
language = "English",
volume = "293",
pages = "1286--1297",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "4",

}

TY - JOUR

T1 - The ubiquitin E3 ligase CHIP promotes proteasomal degradation of the serine/threonine protein kinase PINK1 during staurosporine-induced cell death

AU - Yoo, Lang

AU - Chung, Kwang Chul

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Mutations in the gene for the serine/threonine protein kinase PTEN-induced putative kinase 1 (PINK1) are the second most frequent cause of autosomal recessive Parkinson’s disease (PD). Via its kinase activity, PINK1 regulates neuronal cell survival and mitochondrial quality control. Numerous reports have revealed that PINK1 has diverse and physiologically significant functions, and therefore its activity should be tightly regulated. However, the molecular mechanisms regulating PINK1 stability and the modulator(s) involved have not been elucidated. In this study, we demonstrate that the ubiquitin E3 ligase carboxyl terminus of Hsp70-interacting protein (CHIP) promotes PINK1 ubiquitination and decreases its steady-state levels. Moreover, PINK1 levels were strongly reduced in HEK293 and SH-SY5Y cells exposed to the apoptosis-inducer staurosporine. Of note, we found that this reduction resulted from CHIP-mediated PINK1 ubiquitination. Accordingly, siRNA-mediated CHIP knockdown reduced susceptibility to staurosporine-induced cell death. Taken together, these findings suggest that CHIP plays a role in negative regulation of PINK1 stability and may suppress PINK1’s cytoprotective effect during staurosporine-induced mammalian cell death. We propose that this PINK1 regulatory pathway might contribute to Parkinson’s disease pathogenesis.

AB - Mutations in the gene for the serine/threonine protein kinase PTEN-induced putative kinase 1 (PINK1) are the second most frequent cause of autosomal recessive Parkinson’s disease (PD). Via its kinase activity, PINK1 regulates neuronal cell survival and mitochondrial quality control. Numerous reports have revealed that PINK1 has diverse and physiologically significant functions, and therefore its activity should be tightly regulated. However, the molecular mechanisms regulating PINK1 stability and the modulator(s) involved have not been elucidated. In this study, we demonstrate that the ubiquitin E3 ligase carboxyl terminus of Hsp70-interacting protein (CHIP) promotes PINK1 ubiquitination and decreases its steady-state levels. Moreover, PINK1 levels were strongly reduced in HEK293 and SH-SY5Y cells exposed to the apoptosis-inducer staurosporine. Of note, we found that this reduction resulted from CHIP-mediated PINK1 ubiquitination. Accordingly, siRNA-mediated CHIP knockdown reduced susceptibility to staurosporine-induced cell death. Taken together, these findings suggest that CHIP plays a role in negative regulation of PINK1 stability and may suppress PINK1’s cytoprotective effect during staurosporine-induced mammalian cell death. We propose that this PINK1 regulatory pathway might contribute to Parkinson’s disease pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=85041211941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041211941&partnerID=8YFLogxK

U2 - 10.1074/jbc.M117.803890

DO - 10.1074/jbc.M117.803890

M3 - Article

VL - 293

SP - 1286

EP - 1297

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 4

ER -