PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5

Dae Hee Lee, Daeho Kim, Sung Tae Kim, Soyeon Jeong, Jung Lim Kim, Sang Mi Shim, Ah Jung Heo, Xinxin Song, Zong Sheng Guo, David L. Bartlett, Sang Cheul Oh, Junho Lee, Yoshiro Saito, Bo Yeon Kim, Yong Tae Kwon, Yong J. Lee

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10). In this mechanism, TNFSF10 induces the N-terminal arginylation (Nt-arginylation) of the endoplasmic reticulum (ER)-residing molecular chaperone HSPA5/BiP/GRP78, leading to cytosolic accumulation of Nt-arginylated HSPA5 (R-HSPA5). In parallel, TNFSF10 induces the oxidation of PARK7. Oxidized PARK7 acts as a co-chaperone-like protein that binds the ER-derived chaperone R-HSPA5, a member of the HSPA/HSP70 family. By forming a complex with PARK7 (and possibly misfolded protein cargoes), R-HSPA5 binds SQSTM1 through its Nt-Arg, facilitating self-polymerization of SQSTM1 and the targeting of SQSTM1-cargo complexes to phagophores. The 3-way interaction among PARK7, R-HSPA5, and SQSTM1 is stabilized by the Nt-Arg residue of R-HSPA5. PARK7-deficient cells are impaired in the targeting of R-HSPA5 and SQSTM1 to phagophores and the removal of Ub-conjugated cargoes. Our results suggest that PARK7 functions as a co-chaperone for R-HSPA5 to modulate autophagic removal of misfolded protein cargoes generated by oxidative stress.

Original languageEnglish
JournalAutophagy
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Molecular Chaperones
Proteolysis
Autophagy
Ubiquitin
Proteins
Endoplasmic Reticulum
Oxidative Stress
TNF-Related Apoptosis-Inducing Ligand
Peroxiredoxins
Polymerization
Oxidation-Reduction

Keywords

  • Macroautophagy
  • N-end rule pathway
  • N-terminal arginylation
  • protein quality control
  • proteolysis
  • SQSTM1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5. / Lee, Dae Hee; Kim, Daeho; Kim, Sung Tae; Jeong, Soyeon; Kim, Jung Lim; Shim, Sang Mi; Heo, Ah Jung; Song, Xinxin; Guo, Zong Sheng; Bartlett, David L.; Oh, Sang Cheul; Lee, Junho; Saito, Yoshiro; Kim, Bo Yeon; Kwon, Yong Tae; Lee, Yong J.

In: Autophagy, 01.01.2018.

Research output: Contribution to journalArticle

Lee, DH, Kim, D, Kim, ST, Jeong, S, Kim, JL, Shim, SM, Heo, AJ, Song, X, Guo, ZS, Bartlett, DL, Oh, SC, Lee, J, Saito, Y, Kim, BY, Kwon, YT & Lee, YJ 2018, 'PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5', Autophagy. https://doi.org/10.1080/15548627.2018.1491212
Lee, Dae Hee ; Kim, Daeho ; Kim, Sung Tae ; Jeong, Soyeon ; Kim, Jung Lim ; Shim, Sang Mi ; Heo, Ah Jung ; Song, Xinxin ; Guo, Zong Sheng ; Bartlett, David L. ; Oh, Sang Cheul ; Lee, Junho ; Saito, Yoshiro ; Kim, Bo Yeon ; Kwon, Yong Tae ; Lee, Yong J. / PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5. In: Autophagy. 2018.
@article{79b9e5a58ce14e47a6d6a8cd8b1198d8,
title = "PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5",
abstract = "Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10). In this mechanism, TNFSF10 induces the N-terminal arginylation (Nt-arginylation) of the endoplasmic reticulum (ER)-residing molecular chaperone HSPA5/BiP/GRP78, leading to cytosolic accumulation of Nt-arginylated HSPA5 (R-HSPA5). In parallel, TNFSF10 induces the oxidation of PARK7. Oxidized PARK7 acts as a co-chaperone-like protein that binds the ER-derived chaperone R-HSPA5, a member of the HSPA/HSP70 family. By forming a complex with PARK7 (and possibly misfolded protein cargoes), R-HSPA5 binds SQSTM1 through its Nt-Arg, facilitating self-polymerization of SQSTM1 and the targeting of SQSTM1-cargo complexes to phagophores. The 3-way interaction among PARK7, R-HSPA5, and SQSTM1 is stabilized by the Nt-Arg residue of R-HSPA5. PARK7-deficient cells are impaired in the targeting of R-HSPA5 and SQSTM1 to phagophores and the removal of Ub-conjugated cargoes. Our results suggest that PARK7 functions as a co-chaperone for R-HSPA5 to modulate autophagic removal of misfolded protein cargoes generated by oxidative stress.",
keywords = "Macroautophagy, N-end rule pathway, N-terminal arginylation, protein quality control, proteolysis, SQSTM1",
author = "Lee, {Dae Hee} and Daeho Kim and Kim, {Sung Tae} and Soyeon Jeong and Kim, {Jung Lim} and Shim, {Sang Mi} and Heo, {Ah Jung} and Xinxin Song and Guo, {Zong Sheng} and Bartlett, {David L.} and Oh, {Sang Cheul} and Junho Lee and Yoshiro Saito and Kim, {Bo Yeon} and Kwon, {Yong Tae} and Lee, {Yong J.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1080/15548627.2018.1491212",
language = "English",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",

}

TY - JOUR

T1 - PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5

AU - Lee, Dae Hee

AU - Kim, Daeho

AU - Kim, Sung Tae

AU - Jeong, Soyeon

AU - Kim, Jung Lim

AU - Shim, Sang Mi

AU - Heo, Ah Jung

AU - Song, Xinxin

AU - Guo, Zong Sheng

AU - Bartlett, David L.

AU - Oh, Sang Cheul

AU - Lee, Junho

AU - Saito, Yoshiro

AU - Kim, Bo Yeon

AU - Kwon, Yong Tae

AU - Lee, Yong J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10). In this mechanism, TNFSF10 induces the N-terminal arginylation (Nt-arginylation) of the endoplasmic reticulum (ER)-residing molecular chaperone HSPA5/BiP/GRP78, leading to cytosolic accumulation of Nt-arginylated HSPA5 (R-HSPA5). In parallel, TNFSF10 induces the oxidation of PARK7. Oxidized PARK7 acts as a co-chaperone-like protein that binds the ER-derived chaperone R-HSPA5, a member of the HSPA/HSP70 family. By forming a complex with PARK7 (and possibly misfolded protein cargoes), R-HSPA5 binds SQSTM1 through its Nt-Arg, facilitating self-polymerization of SQSTM1 and the targeting of SQSTM1-cargo complexes to phagophores. The 3-way interaction among PARK7, R-HSPA5, and SQSTM1 is stabilized by the Nt-Arg residue of R-HSPA5. PARK7-deficient cells are impaired in the targeting of R-HSPA5 and SQSTM1 to phagophores and the removal of Ub-conjugated cargoes. Our results suggest that PARK7 functions as a co-chaperone for R-HSPA5 to modulate autophagic removal of misfolded protein cargoes generated by oxidative stress.

AB - Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10). In this mechanism, TNFSF10 induces the N-terminal arginylation (Nt-arginylation) of the endoplasmic reticulum (ER)-residing molecular chaperone HSPA5/BiP/GRP78, leading to cytosolic accumulation of Nt-arginylated HSPA5 (R-HSPA5). In parallel, TNFSF10 induces the oxidation of PARK7. Oxidized PARK7 acts as a co-chaperone-like protein that binds the ER-derived chaperone R-HSPA5, a member of the HSPA/HSP70 family. By forming a complex with PARK7 (and possibly misfolded protein cargoes), R-HSPA5 binds SQSTM1 through its Nt-Arg, facilitating self-polymerization of SQSTM1 and the targeting of SQSTM1-cargo complexes to phagophores. The 3-way interaction among PARK7, R-HSPA5, and SQSTM1 is stabilized by the Nt-Arg residue of R-HSPA5. PARK7-deficient cells are impaired in the targeting of R-HSPA5 and SQSTM1 to phagophores and the removal of Ub-conjugated cargoes. Our results suggest that PARK7 functions as a co-chaperone for R-HSPA5 to modulate autophagic removal of misfolded protein cargoes generated by oxidative stress.

KW - Macroautophagy

KW - N-end rule pathway

KW - N-terminal arginylation

KW - protein quality control

KW - proteolysis

KW - SQSTM1

UR - http://www.scopus.com/inward/record.url?scp=85050557311&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050557311&partnerID=8YFLogxK

U2 - 10.1080/15548627.2018.1491212

DO - 10.1080/15548627.2018.1491212

M3 - Article

C2 - 29976090

AN - SCOPUS:85050557311

JO - Autophagy

JF - Autophagy

SN - 1554-8627

ER -