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

作者：Yoo Young Dong; Mun Su Ran; Ji Chang Hoon; Sung Ki Woon; Kang Keum Young; Heo Ah Jung; Lee Su Hyun; An Jee Young; Hwang Joonsung; Xi Xiang Qun; Ciechanover Aaron^*; Kim Bo Yeon^*; Kwon Yong Tae^*

来源：Proceedings of the National Academy of Sciences, 2018, 115(12): E2716-E2724.

DOI：10.1073/pnas.1719110115

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

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 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.

• 出版日期2018-3-20