p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis

被引：222

作者：

Cha-Molstad, Hyunjoo ^{[1
]}

Yu, Ji Eun ^{[1
,2
]}

Feng, Zhiwei ^{[3
,4
,5
,6
,7
,8
]}

Lee, Su Hyun ^{[9
,10
]}

Kim, Jung Gi ^{[1
,11
]}

Yang, Peng ^{[3
,4
,5
,6
,7
,8
]}

Han, Bitnara ^{[12
]}

Sung, Ki Woon ^{[9
,10
]}

Yoo, Young Dong ^{[9
,10
]}

Hwang, Joonsung ^{[1
]}

McGuire, Terry ^{[3
,4
,5
,6
,7
,8
]}

Shim, Sang Mi ^{[9
,10
]}

Song, Hyun Dong ^{[13
]}

Ganipisetti, Srinivasrao ^{[1
]}

Wang, Nuozhou ^{[3
,4
,5
,6
,7
,8
]}

Jang, Jun Min ^{[9
,10
,18
]}

Lee, Min Jae ^{[14
]}

Kim, Seung Jun ^{[15
]}

Lee, Kyung Ho ^{[1
]}

Hong, Jin Tae ^{[2
]}

Ciechanover, Aaron ^{[9
,10
,16
]}

Mook-Jung, Inhee ^{[13
]}

Kim, Kwang Pyo ^{[12
]}

Xie, Xiang-Qun ^{[3
,4
,5
,6
,7
,8
]}

Kwon, Yong Tae ^{[9
,10
,17
]}

Kim, Bo Yeon ^{[1
,11
]}

机构：

[1] Korea Res Inst Biosci & Biotechnol, World Class Inst, Anticanc Agents Res Ctr, Ochang 28116, Cheongwon, South Korea

[2] Chungbuk Natl Univ, Coll Pharm, Dept Drug Discovery & Dev, Chungbuk 28644, Cheongju, South Korea

[3] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA

[4] Univ Pittsburgh, Sch Pharm, Computat Chem Genom Screening Ctr, Pittsburgh, PA 15260 USA

[5] Univ Pittsburgh, NIDA Natl Ctr Excellence Computat Drug Abuse Res, Pittsburgh, PA 15260 USA

[6] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15260 USA

[7] Univ Pittsburgh, Sch Med, Dept Computat Biol, Pittsburgh, PA 15260 USA

[8] Univ Pittsburgh, Sch Med, Dept Struct Biol, Pittsburgh, PA 15260 USA

[9] Seoul Natl Univ, Coll Med, Prot Metab Med Res Ctr, Seoul 03080, South Korea

[10] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 03080, South Korea

[11] Univ Sci & Technol, Dept Biomol Sci, Daejeon 34113, South Korea

[12] Kyung Hee Univ, Coll Appl Sci, Dept Appl Chem, Yongin 17104, South Korea

[13] Seoul Natl Univ, Coll Med, Dept Biochem & Biomed Sci, Seoul 03080, South Korea

[14] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Dept Biochem & Mol Biol, Seoul 03080, South Korea

[15] Korea Res Inst Biosci & Biotechnol, Dis Target Struct Res Ctr, Daejeon 34141, South Korea

[16] Technion Israel Inst Technol, Fac Med, TICC, IL-31096 Haifa, Israel

[17] Seoul Natl Univ, Coll Med, Ischem Hypox Dis Inst, Seoul 03080, South Korea

[18] Samsung Biol, QC Team Operat Part Sample Managements, Incheon 21987, South Korea

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

ENDOPLASMIC-RETICULUM STRESS; UBIQUITIN LIGASE; TERMINAL ARGINYLATION; MOLECULAR PRINCIPLES; HUNTINGTONS-DISEASE; PROTEIN-FRAGMENTS; STRUCTURAL BASIS; UBR BOX; P62; DEGRADATION;

D O I：

10.1038/s41467-017-00085-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Macroautophagy mediates the selective degradation of proteins and non-proteinaceous cellular constituents. Here, we show that the N-end rule pathway modulates macroautophagy. In this mechanism, the autophagic adapter p62/SQSTM1/Sequestosome-1 is an N-recognin that binds type-1 and type-2 N-terminal degrons (N-degrons), including arginine (Nt-Arg). Both types of N-degrons bind its ZZ domain. By employing three-dimensional modeling, we developed synthetic ligands to p62 ZZ domain. The binding of Nt-Arg and synthetic ligands to ZZ domain facilitates disulfide bond-linked aggregation of p62 and p62 interaction with LC3, leading to the delivery of p62 and its cargoes to the autophagosome. Upon binding to its ligand, p62 acts as a modulator of macroautophagy, inducing autophagosome biogenesis. Through these dual functions, cells can activate p62 and induce selective autophagy upon the accumulation of autophagic cargoes. We also propose that p62 mediates the crosstalk between the ubiquitin-proteasome system and autophagy through its binding Nt-Arg and other N-degrons.

引用

页数：17

共 69 条

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UBR2 of the N-End Rule Pathway Is Required for Chromosome Stability via Histone Ubiquitylation in Spermatocytes and Somatic Cells [J].