이용준 (University of Pittsburgh) | 한빛사논문 > 한빛사

한빛사논문

조회1,345

University of Pittsburgh

CV File 277 kb

Autophagy, Accepted author version posted online: 06 Jul 2018 | https://doi.org/10.1080/15548627.2018.1491212 PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5

Dae-Hee Lee^a,b,c,*, Daeho Kim^d,e*, Sung Tae Kim^d,f, Soyeon Jeong^a, Jung Lim Kim^a, Sang Mi Shim^d, Ah Jung Heo^d, Xinxin Song^c, Zong Sheng Guo^c, David L. Bartlett^c, Sang Cheul Oh^a,b, Junho Lee^e,g, Yoshiro Saito^h, Bo Yeon Kimⁱ,
Yong Tae Kwon^d,j, and Yong J. Lee^c

^aDepartment of Oncology, Korea University Guro Hospital, Seoul, Republic of Korea
^bGraduate School of Medicine, Korea University College of Medicine, Seoul, Republic of Korea;
^cDepartment of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA;
^dProtein Metabolism Medical Research Center and Department of Biomedical Science, College of Medicine, Seoul National University, Seoul, Republic of Korea;
^eDepartment of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea;
^fCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA;
^gThe Institute of Molecular Biology and Genetics, Research Center for Cellulomics, Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea;
^hDepartment of Medical Life Systems, Doshisha University, Kyoto, Japan; iWorld Class Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea;
^jIschemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea

^*These authors equally contributed to this work.

Contact : Yong J. Lee, Department of Surgery, Hillman Cancer Center, University of Pittsburgh, 5117 Centre Ave. Room 1.46C, Pittsburgh, PA 15213, USA;
Yong Tae Kwon, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea;
Bo Yeon Kim, World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 28116, Daejeon, Republic of Korea

Present address for Xinxin Song Department of Obstetrics & Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA

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

논문정보

형식Research article
게재일2018년 07월 (BRIC 등록일 2018-07-12)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

댓글 작성 로그인

CV 열람하기

연락처 보기