Hwang, CS

Kim, JM

Cell Cycle

포항공과대학교

Full Terms & Conditions of access and use can be found athttps://www.tandfonline.com/action/journalInformation?journalCode=kccy20Cell CycleISSN: 1538-4101 (Print) 1551-4005 (Online) Journal homepage: https://www.tandfonline.com/loi/kccy20Crosstalk between the Arg/N-end and Ac/N-endruleJeong-Mok Kim & Cheol-Sang HwangTo cite this article: Jeong-Mok Kim & Cheol-Sang Hwang (2014) Crosstalk between the Arg/N-endand Ac/N-end rule, Cell Cycle, 13:9, 1366-1367, DOI: 10.4161/cc.28751To link to this article:  https://doi.org/10.4161/cc.28751Copyright © 2014 Landes BiosciencePublished online: 03 Apr 2014.Submit your article to this journal Article views: 252View Crossmark dataCiting articles: 7 View citing articles Cell Cycle 13:9, 1366–1367; May 1, 2014; © 2014 Landes Bioscience EditoriaLs: CELL CyCLE FEaturEs1366 Cell Cycle Volume 13 issue 9EditoriaLs: CEL  CyCLE F aturEsProtein degradation in eukaryotic cells is mediated mainly by the ubiquitin (Ub)-proteasome system. One fundamen-tal question in this field is about specific features in a protein that trigger its ubiq-uitylation and subsequent proteasomal degradation? In other words, the problem of degradation signals (degrons).1The first degradation signals to be identified were N-degrons, which com-prised destabilizing N-terminal residues of protein substrates.2 Detailed analysis of the N-degrons gave rise to the N-end rule, which enables the nature of N-terminal residue and its modifications to dictate the in vivo half-life of a protein. In eukary-otes, the N-end rule pathway comprises 2 major branches, the Arg/N-end rule path-way and the Ac/N-end rule pathway.3,4The Arg/N-end rule pathway was the first specific pathway of the Ub system to be discovered.2 This pathway involves, in particular, the N-terminal arginylation of a protein and N-recognins (E3 Ub ligases in eukaryotes). The E3 N-recognins spe-cifically target unacetylated basic (Arg, Lys, His) or bulky hydrophobic (Leu, Phe, Tyr, Trp, Ile) N-terminal residues. The Arg/N-end rule pathway has been implicated in a wide range of functions, including the sensing of small peptides or nitric oxide, protein quality control, DNA repair, meiosis, cardiovascular develop-ment, etc.3,4The other branch, called the Ac/N-end rule pathway, targets for degrada-tion proteins through their Nα-terminally acetylated (Nt-acetylated) residues. In eukaryotes, Nt-acetylation is one of the most common protein modifications, observed in up to 90% of human proteins.5 Despite its abundance and pervasiveness, the biological role of Nt-acetylation in a majority of proteins had been largely unknown. Nt-acetylation was mostly thought to protect a protein from degra-dation. In contrast, it was discovered in 2010 that Nt-acetylation creates specific degrons for the Ac/N-end rule pathway.6This finding has shown that the Nt-acetyl group at the N-termini of many cellular proteins is an entirely new class of degradation signals, termed Ac/N-degrons. Nt-acetylation occurs largely cotranslationally and apparently irrevers-ibly.5 In other words, nearly every protein obtains a specific Ac/N-degron from the moment of its birth. Thus, formed Ac/N-degrons were therefore suggested to be conditionally active, only if they were accessible to Ac/N-recognins, when an Ac/N-degron is not masked through rapid intramolecular folding of a protein or intermolecular assembly with other pro-teins.6 In accordance with this assump-tion, the Ac/N-degron of Cog1, a subunit of the Golgi-localized COG complex, was shown to be sterically shielded by its inter-actions with Cog2, Cog3, and Cog4 in the COG complex, and thereby to moni-tor and control the levels of Cog1 in a cell, relative to those of its binding partners.7 This study provided not only the first example of physiological functions of the Ac/N-end rule pathway, but also a simple scheme for the control of protein quality and stoichiometries.The conditionality of the built-in Ac/N-degrons in the broad range of sub-strates opened up a new question: might there be a proteolytic system to process non-Nt-acetylated proteins by target-ing unmodified “stabilizing” N-terminal residues, which were previously classified in the Arg/N-end rule pathway?3,4 To address this unanswered question, we paid attention to N-terminal methio-nine (Met), because it is present in virtu-ally all nascent polypeptides. We found that Saccharomyces cerevisiae Ubr1 E3 N-recognin and its mouse counterparts UBR1 and UBR2 of the Arg/N-end rule pathway recognized proteins with unac-etylated N-terminal Met, if it is followed by a large second-position ϕ residue (Leu, Ile, Phe, Tyr, Trp)8 (Fig. 1). We further demonstrated that Ubr1 mediated degra-dation of not only quasi-randomly chosen natural proteins (Msn4, Sry1, Arl3, Pre5), but also misfolded proteins by targeting their Met-ϕ residues. Very importantly, the discovery of Met-ϕ degrons greatly expands the substrate range of the Arg/N-end rule pathway, because approximately 15% of all DNA-encoded proteins, in both yeast and mammals, belong to this class of proteins. Furthermore, our find-ing reveals mechanical and functional cross-talks between the Ac/N-end rule pathway and the Arg/N-end rule path-way. Specifically, proteins with Met-ϕ N termini, if Nt-acetylated, can be removed by the Ac/N-end rule pathway or, if they escape Nt-acetylation, by the Arg/N-end rule pathway8 (Fig. 1).The discovery that N-terminal Met acts as a degron suggests that nearly all 20 amino acids are likely to be destabiliz-ing N-terminal residues according to spe-cific sequence context and their states of Nt-acetylation.8 The dual targeting mech-anism of the 2 branches of the N-end rule pathway may be true for conditional deg-radation of many full-length proteins or proteolytic fragments in a cell. The current and further understandings of the N-end *Correspondence to: Cheol-Sang Hwang; Email: cshwang@postech.ac.krSubmitted: 02/11/2014; Accepted: 03/05/2014; Published Online: 04/03/2014http://dx.doi.org/10.4161/cc.28751Comment on: Kim HK, et al. Cell 2014; 156:158-69; PMID:24361105; http://dx.doi.org/10.1016/j.cell.2013.11.031Crosstalk between the Arg/N-end and  Ac/N-end ruleJeong-Mok Kim and Cheol-sang Hwang*department of Life sciences; Pohang university of science and technology; Pohang, Gyeongbuk, south Koreawww.landesbioscience.com Cell Cycle 1367rule pathway may, therefore, account for extensive degradation of most cellular pro-teins by the ubiquitin–proteasome system, including relatively long-lived proteins.References1. Ravid T, et al. Nat Rev Mol Cell Biol 2008; 9:679-90; PMID:18698327; http://dx.doi.org/10.1038/nrm24682. Bachmair A, et al. Science 1986; 234:179-86; PMID:3018930; http://dx.doi.org/10.1126/science.30189303. Varshavsky A. Protein Sci 2011; 20:1298-345; http://dx.doi.org/10.1002/pro.6664. Sriram SM, et al. Nat Rev Mol Cell Biol 2011; 12:735-47; PMID:22016057; http://dx.doi.org/10.1038/nrm32175. Starheim KK, et al. Trends Biochem Sci 2012; 37:152-61; PMID:22405572; http://dx.doi.org/10.1016/j.tibs.2012.02.0036. Hwang CS, et al. Science 2010; 327:973-7; PMID:20110468; http://dx.doi.org/10.1126/science.11831477. Shemorry A, et al. Mol Cell 2013; 50:540-51; PMID:23603116; http://dx.doi.org/10.1016/j.molcel.2013.03.0188. Kim HK, et al. Cell 2014; 156:158-69; PMID:24361105; http://dx.doi.org/10.1016/j.cell.2013.11.031Figure 1. Crosstalk between the arg/N-end rule pathway and the ac/N-end rule pathway. Nearly all nascent proteins bear N-terminal Met due to the auG start codon. the arg/N-end rule pathway targets for degradation proteins with unacetylated N-terminal Met if it is followed by a large hydro-phobic ϕ residue (Leu, ile, Phe, tyr, trp) at position 2. Nt-acetylase catalyzes Nt-acetylation of the Met-ϕ proteins either cotranslationally or posttranslationally, and thereby creates the ac/Met-ϕ degrons for the ac/N-end rule pathway.

Crosstalk between the Arg/N-end and Ac/N-end rule

http://oasis.postech.ac.kr/bitstream/2014.oak/13746/1/Crosstalk%20between%20the%20Arg%20N%20end%20and%20Ac%20N%20end%20rule.pdf

Crosstalk between the Arg/N-end and Ac/N-end rule

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