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 () and Bo Yeon Kim ()
Additional contact information
Hyunjoo Cha-Molstad: Korea Research Institute of Bioscience and Biotechnology
Ji Eun Yu: Korea Research Institute of Bioscience and Biotechnology
Zhiwei Feng: University of Pittsburgh
Su Hyun Lee: Seoul National University
Jung Gi Kim: Korea Research Institute of Bioscience and Biotechnology
Peng Yang: University of Pittsburgh
Bitnara Han: Kyung Hee University
Ki Woon Sung: Seoul National University
Young Dong Yoo: Seoul National University
Joonsung Hwang: Korea Research Institute of Bioscience and Biotechnology
Terry McGuire: University of Pittsburgh
Sang Mi Shim: Seoul National University
Hyun Dong Song: Seoul National University College of Medicine
Srinivasrao Ganipisetti: Korea Research Institute of Bioscience and Biotechnology
Nuozhou Wang: University of Pittsburgh
Jun Min Jang: Seoul National University
Min Jae Lee: Seoul National University College of Medicine
Seung Jun Kim: Korea Research Institute of Bioscience and Biotechnology
Kyung Ho Lee: Korea Research Institute of Bioscience and Biotechnology
Jin Tae Hong: Chungbuk National University
Aaron Ciechanover: Seoul National University
Inhee Mook-Jung: Seoul National University College of Medicine
Kwang Pyo Kim: Kyung Hee University
Xiang-Qun Xie: University of Pittsburgh
Yong Tae Kwon: Seoul National University
Bo Yeon Kim: Korea Research Institute of Bioscience and Biotechnology

Nature Communications, 2017, vol. 8, issue 1, 1-17

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.

Date: 2017
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DOI: 10.1038/s41467-017-00085-7

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