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Nat Commun. 2018 Oct 22;9(1):4373. doi: 10.1038/s41467-018-06878-8.

ZZ-dependent regulation of p62/SQSTM1 in autophagy.

Author information

1
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
2
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
3
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
4
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
5
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea. yok5@snu.ac.kr.
6
Protech Inc., Yongeon 103 Daehangno, Jongno-gu, Seoul, 110-799, Republic of Korea. yok5@snu.ac.kr.
7
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA. tatiana.kutateladze@ucdenver.edu.

Abstract

Autophagic receptor p62 is a critical mediator of cell detoxification, stress response, and metabolic programs and is commonly deregulated in human diseases. The diverse functions of p62 arise from its ability to interact with a large set of ligands, such as arginylated (Nt-R) substrates. Here, we describe the structural mechanism for selective recognition of Nt-R by the ZZ domain of p62 (p62ZZ). We show that binding of p62ZZ to Nt-R substrates stimulates p62 aggregation and macroautophagy and is required for autophagic targeting of p62. p62 is essential for mTORC1 activation in response to arginine, but it is not a direct sensor of free arginine in the mTORC1 pathway. We identified a regulatory linker (RL) region in p62 that binds p62ZZ in vitro and may modulate p62 function. Our findings shed new light on the mechanistic and functional significance of the major cytosolic adaptor protein p62 in two fundamental signaling pathways.

PMID:
30349045
PMCID:
PMC6197226
DOI:
10.1038/s41467-018-06878-8
[Indexed for MEDLINE]
Free PMC Article

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