Open Access
Proceedings of the National Academy of Sciences of the United States of America, volume 115, issue 12, pages E2716-E2724
N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis
Yoo Young Dong
1
,
Mun Su Ran
1
,
Ji Chang Hoon
1
,
Sung Ki Woon
1
,
Kang Keum Young
1
,
Heo Ah Jung
1
,
Lee Su-Hyun
1
,
An Jee-Young
2
,
Hwang Joonsung
3
,
Xie Xiang-Qun
4, 5, 6, 7, 8
,
Ciechanover Aaron
1, 9
,
Kim Bo-Yeon
3
,
Kwon Yong Tae
1, 10
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
Department of Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260;
|
6
Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260;
|
7
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260;
|
8
National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15260;
|
10
Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Jongno-gu, 03080 Seoul, Korea
|
Publication type: Journal Article
Publication date: 2018-03-05
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 11.1
ISSN: 00278424, 10916490
PubMed ID:
29507222
Multidisciplinary
Abstract
Significance Conjugation of the amino acid l-arginine (l-Arg) to the protein N termini is a universal posttranslational modification in eukaryotes, yet its functions remain poorly understood. Previous studies showed that the N-terminal Arg of arginylated substrates is bound by N-recognins to induce substrate ubiquitination and proteasomal degradation via the N-end rule pathway of the ubiquitin (Ub)-proteasome system (UPS). Here, we show that the same Nt-Arg residues of arginylated proteins modulate proteolytic flux via macroautophagy when misfolded proteins accumulate beyond the UPS’s capacity. Their Nt-Arg residues bind and allosterically activate the autophagic adaptor p62/STQSM/Sequestosome-1, facilitating cargo collection and lysosomal degradation. Our results suggest that the Nt-Arg proteome of arginylated proteins contributes to reprogramming global proteolytic flux when the UPS is in trouble. 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.
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Yoo Y. D. et al. N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis // Proceedings of the National Academy of Sciences of the United States of America. 2018. Vol. 115. No. 12. p. E2716-E2724.
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Yoo Y. D., Mun S. R., Ji C. H., Sung K. W., Kang K. Y., Heo A. J., Lee S., An J., Hwang J., Xie X., Ciechanover A., Kim B., Kwon Y. T. N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis // Proceedings of the National Academy of Sciences of the United States of America. 2018. Vol. 115. No. 12. p. E2716-E2724.
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TY - JOUR
DO - 10.1073/pnas.1719110115
UR - https://doi.org/10.1073%2Fpnas.1719110115
TI - N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis
T2 - Proceedings of the National Academy of Sciences of the United States of America
AU - Yoo, Young Dong
AU - Mun, Su Ran
AU - Ji, Chang Hoon
AU - Sung, Ki Woon
AU - Kang, Keum Young
AU - Heo, Ah Jung
AU - Lee, Su-Hyun
AU - An, Jee-Young
AU - Hwang, Joonsung
AU - Xie, Xiang-Qun
AU - Ciechanover, Aaron
AU - Kim, Bo-Yeon
AU - Kwon, Yong Tae
PY - 2018
DA - 2018/03/05 00:00:00
PB - Proceedings of the National Academy of Sciences (PNAS)
SP - E2716-E2724
IS - 12
VL - 115
PMID - 29507222
SN - 0027-8424
SN - 1091-6490
ER -
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@article{2018_Yoo,
author = {Young Dong Yoo and Su Ran Mun and Chang Hoon Ji and Ki Woon Sung and Keum Young Kang and Ah Jung Heo and Su-Hyun Lee and Jee-Young An and Joonsung Hwang and Xiang-Qun Xie and Aaron Ciechanover and Bo-Yeon Kim and Yong Tae Kwon},
title = {N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2018},
volume = {115},
publisher = {Proceedings of the National Academy of Sciences (PNAS)},
month = {mar},
url = {https://doi.org/10.1073%2Fpnas.1719110115},
number = {12},
pages = {E2716--E2724},
doi = {10.1073/pnas.1719110115}
}
Cite this
MLA
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Yoo, Young Dong, et al. “N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis.” Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 12, Mar. 2018, pp. E2716-E2724. https://doi.org/10.1073%2Fpnas.1719110115.