N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis.
N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis.
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N 端精氨酸化产生双峰降解决定子，调节自噬蛋白水解。
DOI：
10.1073/pnas.1719110115
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发表时间：
2018
影响因子：
11.1
通讯作者：
Kwon,YongTae
中科院分区：
文献类型：
--
作者：
Yoo,YoungDong;Mun,SuRan;Ji,ChangHoon;Sung,KiWoon;Kang,KeumYoung;Heo,AhJung;Lee,SuHyun;An,JeeYoung;Hwang,Joonsung;Xie,Xiang-Qun;Ciechanover,Aaron;Kim,BoYeon;Kwon,YongTae
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 acidl-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.
