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

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dc.contributor.authorY D Yoo-
dc.contributor.authorS R Mun-
dc.contributor.authorC H Ji-
dc.contributor.authorK W Sung-
dc.contributor.authorK Y Kang-
dc.contributor.authorA J Heo-
dc.contributor.authorS H Lee-
dc.contributor.authorJ Y An-
dc.contributor.authorJoonsung Hwang-
dc.contributor.authorX Q Xie-
dc.contributor.authorA Ciechanover-
dc.contributor.authorBo Yeon Kim-
dc.contributor.authorY T Kwon-
dc.date.accessioned2018-04-19T05:19:15Z-
dc.date.available2018-04-19T05:19:15Z-
dc.date.issued2018-
dc.identifier.issn0027-8424-
dc.identifier.uri10.1073/pnas.1719110115ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/17798-
dc.description.abstractThe 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 Ntarginylation, 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 cellularwastes tomacroautophagy 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-
dc.publisherNatl Acad Sciences-
dc.titleN-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis-
dc.title.alternativeN-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis-
dc.typeArticle-
dc.citation.titleProceedings of National Academy of Sciences of United States of America-
dc.citation.number12-
dc.citation.endPagee2724-
dc.citation.startPagee2716-
dc.citation.volume115-
dc.contributor.affiliatedAuthorJoonsung Hwang-
dc.contributor.affiliatedAuthorBo Yeon Kim-
dc.contributor.alternativeName유영동-
dc.contributor.alternativeName문수란-
dc.contributor.alternativeName지창훈-
dc.contributor.alternativeName성기운-
dc.contributor.alternativeName강금영-
dc.contributor.alternativeName허아정-
dc.contributor.alternativeName이수현-
dc.contributor.alternativeName안지영-
dc.contributor.alternativeName황준성-
dc.contributor.alternativeNameXie-
dc.contributor.alternativeNameCiechanover-
dc.contributor.alternativeName김보연-
dc.contributor.alternativeName권용태-
dc.identifier.bibliographicCitationProceedings of National Academy of Sciences of United States of America, vol. 115, no. 12, pp. e2716-e2724-
dc.identifier.doi10.1073/pnas.1719110115-
dc.subject.keywordATE1 R-transferase-
dc.subject.keywordN-end rule pathway-
dc.subject.keywordmacroautophagy-
dc.subject.keywordp62/STQSM/Sequestosome-1-
dc.subject.keywordubiquitin-proteasome system-
dc.subject.localATE1 R-transferase-
dc.subject.localN-end rule pathway-
dc.subject.localmacroautophagy-
dc.subject.localMacroautophagy-
dc.subject.localp62/STQSM/Sequestosome-1-
dc.subject.localubiquitin-proteasome system-
dc.subject.localUbiquitin-proteasome system-
dc.description.journalClassY-
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