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.
Bibliographical noteFunding Information:
This work was supported by the Ministry of Science ICT and Future Planning [CAP-16-03-KRIBB]; Ministry of Science ICT and Future Planning [project no. 2012M3A9B6055305]; National Cancer Institute [R03CA212125]; National Cancer Institute [R03CA205267]; National Cancer Institute [R01CA140554]; National Research Foundation of Korea [2017R1A6A3A11032084]; National Research Foundation of Korea [NRF-2016R1A2B3011389]; National Research Foundation of Korea [2015R1D1A1A01058303]; UPCI Core Facility [P30CA047904].
We appreciate Hosun Kim (Seoul National University) for her editorial assistance and Jeong Hun Kim (Sahmyook University) for technical assistance in confocal analyses. This work was supported by National Cancer Institute grants R01CA140554, R03CA205267, and R03CA212125 (to Y.J.L), the Basic Science Research Programs of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) (NRF-2016R1A2B3011389 to Y. T.K., 2015R1D1A1A01058303 to D.H.L., and 2017R1A6A3A11032084 to S.M.S), the Brain Korea 21 PLUS Program (to SNU), SNU Nobel Laureates Invitation Program, and the Bio and Medical Technology Development Program (project no. 2012M3A9B6055305) through the MSIT, the R&D Convergence Program (CAP-16-03-KRIBB) of National Research Council of Science & Technology (NST), and KRIBB Research Initiative Program (to B.Y.K). This project also used the UPCI Core Facility and was supported in part by the award P30CA047904 (to Y.J.L).
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- N-end rule pathway
- N-terminal arginylation
- protein quality control
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology