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Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2716-E2724. doi: 10.1073/pnas.1719110115. Epub 2018 Mar 5.

N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis.

Author information

1
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Jongno-gu, 03080 Seoul, Korea.
2
Center for Genome Engineering, Institute for Basic Science, Yuseong-gu, 34126 Daejeon, Korea.
3
Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 28116 Cheongju, Korea.
4
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15260.
5
National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15260.
6
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260.
7
Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260.
8
Department of Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260.
9
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Jongno-gu, 03080 Seoul, Korea; aaroncie@technion.ac.il bykim@kribb.re.kr yok5@snu.ac.kr.
10
Technion Integrated Cancer Center, Faculty of Medicine, Technion-Israel Institute of Technology, 31096 Haifa, Israel.
11
Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 28116 Cheongju, Korea; aaroncie@technion.ac.il bykim@kribb.re.kr yok5@snu.ac.kr.
12
Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Jongno-gu, 03080 Seoul, Korea.

Abstract

The conjugation of amino acids to the protein N termini is universally observed in eukaryotes and prokaryotes, yet its functions remain poorly understood. In eukaryotes, the amino acid l-arginine (l-Arg) is conjugated to N-terminal Asp (Nt-Asp), Glu, Gln, Asn, and Cys, directly or associated with posttranslational modifications. Following Nt-arginylation, the Nt-Arg is recognized by UBR boxes of N-recognins such as UBR1, UBR2, UBR4/p600, and UBR5/EDD, leading to substrate ubiquitination and proteasomal degradation via the N-end rule pathway. It has been a mystery, however, why studies for the past five decades identified only a handful of Nt-arginylated substrates in mammals, although five of 20 principal amino acids are eligible for arginylation. Here, we show that the Nt-Arg functions as a bimodal degron that directs substrates to either the ubiquitin (Ub)-proteasome system (UPS) or macroautophagy depending on physiological states. In normal conditions, the arginylated forms of proteolytic cleavage products, D101-CDC6 and D1156-BRCA1, are targeted to UBR box-containing N-recognins and degraded by the proteasome. However, when proteostasis by the UPS is perturbed, their Nt-Arg redirects these otherwise cellular wastes to macroautophagy through its binding to the ZZ domain of the autophagic adaptor p62/STQSM/Sequestosome-1. Upon binding to the Nt-Arg, p62 acts as an autophagic N-recognin that undergoes self-polymerization, facilitating cargo collection and lysosomal degradation of p62-cargo complexes. A chemical mimic of Nt-Arg redirects Ub-conjugated substrates from the UPS to macroautophagy and promotes their lysosomal degradation. Our results suggest that the Nt-Arg proteome of arginylated proteins contributes to reprogramming global proteolytic flux under stresses.

KEYWORDS:

ATE1 R-transferase; N-end rule pathway; macroautophagy; p62/STQSM/Sequestosome-1; ubiquitin-proteasome system

PMID:
29507222
PMCID:
PMC5866579
DOI:
10.1073/pnas.1719110115
[Indexed for MEDLINE]
Free PMC Article

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