P62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis

Hyunjoo Cha-Molstad; Ji Eun Yu; Zhiwei Feng; Su Hyun Lee; Jung Gi Kim; Peng Yang; Bitnara Han; Ki Woon Sung; Young Dong Yoo; Joonsung Hwang; Terry McGuire; Sang Mi Shim; Hyun Dong Song; Srinivasrao Ganipisetti; Nuozhou Wang; Jun Min Jang; Min Jae Lee; Seung Jun Kim; Kyung Ho Lee; Jin Tae Hong; Aaron Ciechanover; Inhee Mook-Jung; Kwang Pyo Kim; Xiang Qun Xie; Yong Tae Kwon; Bo Yeon Kim

doi:10.1038/s41467-017-00085-7

P62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis

Hyunjoo Cha-Molstad, Ji Eun Yu, Zhiwei Feng, Su Hyun Lee, Jung Gi Kim, Peng Yang, Bitnara Han, Ki Woon Sung, Young Dong Yoo, Joonsung Hwang, Terry McGuire, Sang Mi Shim, Hyun Dong Song, Srinivasrao Ganipisetti, Nuozhou Wang, Jun Min Jang, Min Jae Lee, Seung Jun Kim, Kyung Ho Lee, Jin Tae HongAaron Ciechanover, Inhee Mook-Jung, Kwang Pyo Kim, Xiang Qun Xie, Yong Tae Kwon, Bo Yeon Kim

Medicine

Technion - Israel Institute of Technology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	102
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00085-7
State	Published - 1 Dec 2017

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-017-00085-7

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Cha-Molstad, H., Yu, J. E., Feng, Z., Lee, S. H., Kim, J. G., Yang, P., Han, B., Sung, K. W., Yoo, Y. D., Hwang, J., McGuire, T., Shim, S. M., Song, H. D., Ganipisetti, S., Wang, N., Jang, J. M., Lee, M. J., Kim, S. J., Lee, K. H., ... Kim, B. Y. (2017). P62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nature Communications, 8(1), Article 102. https://doi.org/10.1038/s41467-017-00085-7

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title = "P62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis",

abstract = "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.",

author = "Hyunjoo Cha-Molstad and Yu, \{Ji Eun\} and Zhiwei Feng and Lee, \{Su Hyun\} and Kim, \{Jung Gi\} and Peng Yang and Bitnara Han and Sung, \{Ki Woon\} and Yoo, \{Young Dong\} and Joonsung Hwang and Terry McGuire and Shim, \{Sang Mi\} and Song, \{Hyun Dong\} and Srinivasrao Ganipisetti and Nuozhou Wang and Jang, \{Jun Min\} and Lee, \{Min Jae\} and Kim, \{Seung Jun\} and Lee, \{Kyung Ho\} and Hong, \{Jin Tae\} and Aaron Ciechanover and Inhee Mook-Jung and Kim, \{Kwang Pyo\} and Xie, \{Xiang Qun\} and Kwon, \{Yong Tae\} and Kim, \{Bo Yeon\}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00085-7",

language = "الإنجليزيّة",

volume = "8",

journal = "Nature Communications",

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Cha-Molstad, H, Yu, JE, Feng, Z, Lee, SH, Kim, JG, Yang, P, Han, B, Sung, KW, Yoo, YD, Hwang, J, McGuire, T, Shim, SM, Song, HD, Ganipisetti, S, Wang, N, Jang, JM, Lee, MJ, Kim, SJ, Lee, KH, Hong, JT, Ciechanover, A, Mook-Jung, I, Kim, KP, Xie, XQ, Kwon, YT & Kim, BY 2017, 'P62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis', Nature Communications, vol. 8, no. 1, 102. https://doi.org/10.1038/s41467-017-00085-7

TY - JOUR

T1 - P62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis

AU - Cha-Molstad, Hyunjoo

AU - Yu, Ji Eun

AU - Feng, Zhiwei

AU - Lee, Su Hyun

AU - Kim, Jung Gi

AU - Yang, Peng

AU - Han, Bitnara

AU - Sung, Ki Woon

AU - Yoo, Young Dong

AU - Hwang, Joonsung

AU - McGuire, Terry

AU - Shim, Sang Mi

AU - Song, Hyun Dong

AU - Ganipisetti, Srinivasrao

AU - Wang, Nuozhou

AU - Jang, Jun Min

AU - Lee, Min Jae

AU - Kim, Seung Jun

AU - Lee, Kyung Ho

AU - Hong, Jin Tae

AU - Ciechanover, Aaron

AU - Mook-Jung, Inhee

AU - Kim, Kwang Pyo

AU - Xie, Xiang Qun

AU - Kwon, Yong Tae

AU - Kim, Bo Yeon

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-017-00085-7

DO - 10.1038/s41467-017-00085-7

M3 - مقالة

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 102

ER -

P62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

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