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 journalArticlepeer-review

21 Scopus citations

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 (US)
Pages (from-to)1870-1885
Number of pages16
JournalAutophagy
Volume14
Issue number11
DOIs
StatePublished - Nov 2 2018
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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