Browse > Article
http://dx.doi.org/10.14348/molcells.2016.2329

N-Terminal Acetylation-Targeted N-End Rule Proteolytic System: The Ac/N-End Rule Pathway  

Lee, Kang-Eun (Department of Life Sciences, Pohang University of Science and Technology)
Heo, Ji-Eun (Department of Life Sciences, Pohang University of Science and Technology)
Kim, Jeong-Mok (Department of Life Sciences, Pohang University of Science and Technology)
Hwang, Cheol-Sang (Department of Life Sciences, Pohang University of Science and Technology)
Publication Information
Molecules and Cells / v.39, no.3, 2016 , pp. 169-178 More about this Journal
Abstract
Although $N{\alpha}$-terminal acetylation (Nt-acetylation) is a pervasive protein modification in eukaryotes, its general functions in a majority of proteins are poorly understood. In 2010, it was discovered that Nt-acetylation creates a specific protein degradation signal that is targeted by a new class of the N-end rule proteolytic system, called the Ac/N-end rule pathway. Here, we review recent advances in our understanding of the mechanism and biological functions of the Ac/N-end rule pathway, and its crosstalk with the Arg/N-end rule pathway (the classical N-end rule pathway).
Keywords
degron; N-end rule; N-terminal acetylation; proteolysis; ubiquitin;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Pena, M.M., Melo, S.P., Xing, Y.Y., White, K., Barbour, K.W., and Berger, F.G. (2009). The intrinsically disordered N-terminal domain of thymidylate synthase targets the enzyme to the ubiquitin- independent proteasomal degradation pathway. J. Biol. Chem. 284, 31597-31607.   DOI
2 Pesaresi, P., Gardner, N.A., Masiero, S., Dietzmann, A., Eichacker, L., Wickner, R., Salamini, F., and Leister, D. (2003). Cytoplasmic N-terminal protein acetylation is required for efficient photosynthesis in Arabidopsis. Plant Cell 15, 1817-1832.   DOI
3 Pezza, J.A., Langseth, S.X., Raupp Yamamoto, R., Doris, S.M., Ulin, S.P., Salomon, A.R., and Serio, T.R. (2009). The NatA acetyltransferase couples Sup35 prion complexes to the [PSI+] phenotype. Mol. Biol. Cell 20, 1068-1080.   DOI
4 Piatkov, K.I., Vu, T.M., Hwang, C.S., and Varshavsky, A. (2015). Formyl-methionine as a degradation signal at the N-termini of bacterial proteins. Microbia Cell 2, 376-393.   DOI
5 Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J.M., Madeo, F., and Kroemer, G. (2015). Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805-821.   DOI
6 Polevoda, B., Norbeck, J., Takakura, H., Blomberg, A., and Sherman, F. (1999). Identification and specificities of N-terminal acetyltransferases from Saccharomyces cerevisiae. EMBO J. 18, 6155-6168.   DOI
7 Polevoda, B., Hoskins, J., and Sherman, F. (2009). Properties of Nat4, an N(alpha)-acetyltransferase of Saccharomyces cerevisiae that modifies N termini of histones H2A and H4. Mol. Cell. Biol. 29, 2913-2924.   DOI
8 Ravid, T., and Hochstrasser, M. (2008). Diversity of degradation signals in the ubiquitin-proteasome system. Nat. Rev. Mol. Cell Biol. 9, 679-690.   DOI
9 Rope, A.F., Wang, K., Evjenth, R., Xing, J., Johnston, J.J., Swensen, J.J., Johnson, W.E., Moore, B., Huff, C.D., Bird, L.M., et al. (2011). Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. Am. J. Hum. Genet. 89, 28-43.   DOI
10 Sawant, S.V., Kiran, K., Singh, P.K., and Tuli, R. (2001). Sequence architecture downstream of the initiator codon enhances gene expression and protein stability in plants. Plant Physiol. 126, 1630-1636.   DOI
11 Scazzari, M., Amm, I., and Wolf, D.H. (2015). Quality control of a cytoplasmic protein complex: chaperone motors and the ubiquitin- proteasome system govern the fate of orphan fatty acid synthase subunit Fas2 of yeast. J. Biol. Chem. 290, 4677-4687.   DOI
12 Scott, D.C., Monda, J.K., Bennett, E.J., Harper, J.W., and Schulman, B.A. (2011). N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex. Science 334, 674-678.   DOI
13 Seo, J.H., Cha, J.H., Park, J.H., Jeong, C.H., Park, Z.Y., Lee, H.S., Oh, S.H., Kang, J.H., Suh, S.W., Kim, K.H., et al. (2010). Arrest defective 1 autoacetylation is a critical step in its ability to stimulate cancer cell proliferation. Cancer Res. 70, 4422-4432.   DOI
14 Setty, S.R., Strochlic, T.I., Tong, A.H., Boone, C., and Burd, C.G. (2004). Golgi targeting of ARF-like GTPase Arl3p requires its Nalpha-acetylation and the integral membrane protein Sys1p. Nat. Cell Biol. 6, 414-419.   DOI
15 Shemorry, A., Hwang, C.S., and Varshavsky, A. (2013). Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway. Mol. Cell 50, 540-551.   DOI
16 Silva, R.D., and Martinho, R.G. (2015). Developmental roles of protein N-terminal acetylation. Proteomics 15, 2402-2409.   DOI
17 Swanson, R., Locher, M., and Hochstrasser, M. (2001). A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes Dev. 15, 2660-2674.   DOI
18 Sriram, S.M., Kim, B.Y., and Kwon, Y.T. (2011). The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat. Rev. Mol. Cell Biol. 12, 735-747.   DOI
19 Starheim, K.K., Gevaert, K., and Arnesen, T. (2012). Protein Nterminal acetyltransferases: when the start matters. Trends Biochem. Sci. 37, 152-161.   DOI
20 Sundberg, T.B., Darricarrere, N., Cirone, P., Li, X., McDonald, L., Mei, X., Westlake, C.J., Slusarski, D.C., Beynon, R.J., and Crews, C.M. (2011). Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37. Chem. Biol. 18, 1300-1311.   DOI
21 Tasaki, T., Sriram, S.M., Park, K.S., and Kwon, Y.T. (2012). The Nend rule pathway. Ann. Rev. Biochem. 81, 261-289.   DOI
22 Van Damme, P., Hole, K., Pimenta-Marques, A., Helsens, K., Vandekerckhove, J., Martinho, R.G., Gevaert, K., and Arnesen, T. (2011). NatF contributes to an evolutionary shift in protein Nterminal acetylation and is important for normal chromosome segregation. PLoS Genet. 7, e1002169.   DOI
23 Van Damme, P., Lasa, M., Polevoda, B., Gazquez, C., Elosegui- Artola, A., Kim, D.S., De Juan-Pardo, E., Demeyer, K., Hole, K., Larrea, E., et al. (2012). N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc. Natl. Acad. Sci. USA 109, 12449-12454.   DOI
24 Varshavsky, A. (2011). The N-end rule pathway and regulation by proteolysis. Protein Sci. 20, 1298-1345.   DOI
25 Xu, F., Huang, Y., Li, L., Gannon, P., Linster, E., Huber, M., Kapos, P., Bienvenut, W., Polevoda, B., Meinnel, T., et al. (2015). Two N-terminal acetyltransferases antagonistically regulate the stability of a nod-like receptor in Arabidopsis. Plant Cell 27, 1547-1562.   DOI
26 Wang, L., Dong, H., Soroka, C.J., Wei, N., Boyer, J.L., and Hochstrasser, M. (2008). Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II. Hepatology 48, 1558-1569.   DOI
27 Weits, D.A., Giuntoli, B., Kosmacz, M., Parlanti, S., Hubberten, H.M., Riegler, H., Hoefgen, R., Perata, P., van Dongen, J.T., and Licausi, F. (2014). Plant cysteine oxidases control the oxygendependent branch of the N-end-rule pathway. Nat. Commun. 5, 3425.   DOI
28 Xu, Z., Payoe, R., and Fahlman, R.P. (2012). The C-terminal proteolytic fragment of the breast cancer susceptibility type 1 protein (BRCA1) is degraded by the N-end rule pathway. J. Biol. Chem. 287, 7495-7502.   DOI
29 Yamano, K., and Youle, R.J. (2013). PINK1 is degraded through the N-end rule pathway. Autophagy 9, 1758-1769.   DOI
30 Yi, C.H., Pan, H., Seebacher, J., Jang, I.H., Hyberts, S.G., Heffron, G.J., Vander Heiden, M.G., Yang, R., Li, F., Locasale, J.W., et al. (2011). Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival. Cell 146, 607-620.   DOI
31 Zattas, D., and Hochstrasser, M. (2015). Ubiquitin-dependent protein degradation at the yeast endoplasmic reticulum and nuclear envelope. Crit. Rev. Biochem. Mol. Biol. 50, 1-17.   DOI
32 Zattas, D., Adle, D.J., Rubenstein, E.M., and Hochstrasser, M. (2013). N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin-ligase activity toward luminal ER substrates. Mol. Biol. Cell 24, 890-900.   DOI
33 Zenker, M., Mayerle, J., Lerch, M.M., Tagariello, A., Zerres, K., Durie, P.R., Beier, M., Hulskamp, G., Guzman, C., Rehder, H., et al. (2005). Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nat. Genet. 37, 1345-1350.   DOI
34 Zavacki, A.M., Arrojo, E.D.R., Freitas, B.C., Chung, M., Harney, J.W., Egri, P., Wittmann, G., Fekete, C., Gereben, B., and Bianco, A.C. (2009). The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine deiodinase. Mol. Cell. Biol. 29, 5339-5347.   DOI
35 Zelcer, N., Sharpe, L.J., Loregger, A., Kristiana, I., Cook, E.C., Phan, L., Stevenson, J., and Brown, A.J. (2014). The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway. Mol. Cell. Biol. 34, 1262-1270.   DOI
36 Zeng, L., Zhang, Q., Li, S., Plotnikov, A.N., Walsh, M.J., and Zhou, M.M. (2010). Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466, 258-262.   DOI
37 Zhang, Z., Kulkarni, K., Hanrahan, S.J., Thompson, A.J., and Barford, D. (2010). The APC/C subunit Cdc16/Cut9 is a contiguous tetratricopeptide repeat superhelix with a homo-dimer interface similar to Cdc27. EMBO J. 29, 3733-3744.   DOI
38 Aksnes, H., Van Damme, P., Goris, M., Starheim, K.K., Marie, M., Stove, S.I., Hoel, C., Kalvik, T.V., Hole, K., Glomnes, N., et al. (2015c). An organellar nalpha-acetyltransferase, naa60, acetylates cytosolic N termini of transmembrane proteins and maintains Golgi integrity. Cell Rep. 10, 1362-1374.   DOI
39 Aksnes, H., Drazic, A., and Arnesen, T. (2015a). (Hyper)tension release by N-terminal acetylation. Trends Biochem. Sci. 40, 422-424.   DOI
40 Aksnes, H., Hole, K., and Arnesen, T. (2015b). Molecular, cellular, and physiological significance of N-terminal acetylation. Int. Rev. Cell Mol. Biol. 316, 267-305.   DOI
41 Arnesen, T., Van Damme, P., Polevoda, B., Helsens, K., Evjenth, R., Colaert, N., Varhaug, J.E., Vandekerckhove, J., Lillehaug, J.R., Sherman, F., et al. (2009). Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc. Natl. Acad. Sci. USA 106, 8157-8162.   DOI
42 Arnesen, T., Starheim, K.K., Van Damme, P., Evjenth, R., Dinh, H., Betts, M.J., Ryningen, A., Vandekerckhove, J., Gevaert, K., and Anderson, D. (2010). The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation. Mol. Cell. Biol. 30, 1898-1909.   DOI
43 Bachmair, A., Finley, D., and Varshavsky, A. (1986). In vivo half-life of a protein is a function of its amino-terminal residue. Science 234, 179-186.   DOI
44 Bagadi, S.A., Prasad, C.P., Srivastava, A., Prashad, R., Gupta, S.D., and Ralhan, R. (2007). Frequent loss of Dab2 protein and infrequent promoter hypermethylation in breast cancer. Breast Cancer Res. Treat. 104, 277-286.   DOI
45 Behnia, R., Panic, B., Whyte, J.R., and Munro, S. (2004). Targeting of the Arf-like GTPase Arl3p to the Golgi requires N-terminal acetylation and the membrane protein Sys1p. Nat. Cell Biol. 6, 405-413.   DOI
46 Bodenstein, J., Sunahara, R.K., and Neubig, R.R. (2007). Nterminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Mol. Pharmacol. 71, 1040-1050.   DOI
47 Beltran-Alvarez, P., Tarradas, A., Chiva, C., Perez-Serra, A., Batlle, M., Perez-Villa, F., Schulte, U., Sabido, E., Brugada, R., and Pagans, S. (2014). Identification of N-terminal protein acetylation and arginine methylation of the voltage-gated sodium channel in end-stage heart failure human heart. J. Mol. Cell. Cardiol. 76, 126-129.   DOI
48 Bhattacharjee, A., Majumdar, U., Maity, D., Sarkar, T.S., Goswami, A.M., Sahoo, R., and Ghosh, S. (2009). In vivo protein tyrosine nitration in S. cerevisiae: identification of tyrosine-nitrated proteins in mitochondria. Biochem. Biophys. Res. Commun. 388, 612-617.   DOI
49 Bischof, S., Baerenfaller, K., Wildhaber, T., Troesch, R., Vidi, P.A., Roschitzki, B., Hirsch-Hoffmann, M., Hennig, L., Kessler, F., Gruissem, W., et al. (2011). Plastid proteome assembly without Toc159: photosynthetic protein import and accumulation of Nacetylated plastid precursor proteins. Plant Cell 23, 3911-3928.   DOI
50 Cha-Molstad, H., Sung, K.S., Hwang, J., Kim, K.A., Yu, J.E., Yoo, Y.D., Jang, J.M., Han, D.H., Molstad, M., Kim, J.G., et al. (2015). Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding. Nat. Cell Biol. 17, 917-929.   DOI
51 Chen, S., Vetro, J.A., and Chang, Y.H. (2002). The specificity in vivo of two distinct methionine aminopeptidases in Saccharomyces cerevisiae. Arch. Biochem. Biophys. 398, 87-93.   DOI
52 Chen, Y.L., Kuo, M.H., Lin, P.Y., Chuang, W.L., Hsu, C.C., Chu, P.Y., Lee, C.H., Huang, T.H., Leu, Y.W., and Hsiao, S.H. (2013). ENSA expression correlates with attenuated tumor propagation in liver cancer. Biochem. Biophys. Res. Commun. 442, 56-61.   DOI
53 Ditzel, M., Wilson, R., Tenev, T., Zachariou, A., Paul, A., Deas, E., and Meier, P. (2003). Degradation of DIAP1 by the N-end rule pathway is essential for regulating apoptosis. Nat. Cell Biol. 5, 467-473.   DOI
54 Ciechanover, A., and Ben-Saadon, R. (2004). N-terminal ubiquitination: more protein substrates join in. Trends Cell Biol. 14, 103-106.   DOI
55 Ciechanover, A., and Kwon, Y.T. (2015). Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp. Mol. Med. 47, e147.   DOI
56 Dinh, T.V., Bienvenut, W.V., Linster, E., Feldman-Salit, A., Jung, V.A., Meinnel, T., Hell, R., Giglione, C., and Wirtz, M. (2015). Molecular identification and functional characterization of the first Nalpha-acetyltransferase in plastids by global acetylome profiling. Proteomics 15, 2426-2435.   DOI
57 Doblas, V.G., Amorim-Silva, V., Pose, D., Rosado, A., Esteban, A., Arro, M., Azevedo, H., Bombarely, A., Borsani, O., Valpuesta, V., et al. (2013). The SUD1 gene encodes a putative E3 ubiquitin ligase and is a positive regulator of 3-hydroxy-3-methylglutaryl coenzyme a reductase activity in Arabidopsis. Plant Cell 25, 728-743.   DOI
58 Dohmen, R.J. (2015). Starting with a degron: N-terminal formylmethionine of nascent bacterial proteins contributes to their proteolytic control. Microbia Cell 2, 356-359.   DOI
59 Dorfel, M.J., and Lyon, G.J. (2015). The biological functions of Naa10 - From amino-terminal acetylation to human disease. Gene 567, 103-131.   DOI
60 Dougan, D.A., Micevski, D., and Truscott, K.N. (2012). The N-end rule pathway: from recognition by N-recognins, to destruction by AAA+proteases. Biochim. Biophys. Acta 1823, 83-91.   DOI
61 Foresti, O., Ruggiano, A., Hannibal-Bach, H.K., Ejsing, C.S., and Carvalho, P. (2013). Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. Elife 2, e00953.
62 Erickson, S.L., Corpuz, E.O., Maloy, J.P., Fillman, C., Webb, K., Bennett, E.J., and Lykke-Andersen, J. (2015). Competition between decapping complex formation and ubiquitin-mediated proteasomal degradation controls human Dcp2 decapping activity. Mol. Cell. Biol. 35, 2144-2153.   DOI
63 Esmailpour, T., Riazifar, H., Liu, L., Donkervoort, S., Huang, V.H., Madaan, S., Shoucri, B.M., Busch, A., Wu, J., Towbin, A., et al. (2014). A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome. J. Med. Genet. 51, 185-196.   DOI
64 Ferrandez-Ayela, A., Micol-Ponce, R., Sanchez-Garcia, A.B., Alonso-Peral, M.M., Micol, J.L., and Ponce, M.R. (2013). Mutation of an Arabidopsis NatB N-alpha-terminal acetylation complex component causes pleiotropic developmental defects. PLoS One 8, e80697.   DOI
65 Forte, G.M., Pool, M.R., and Stirling, C.J. (2011). N-terminal acetylation inhibits protein targeting to the endoplasmic reticulum. PLoS Biol. 9, e1001073.   DOI
66 Garrels, J.I., McLaughlin, C.S., Warner, J.R., Futcher, B., Latter, G.I., Kobayashi, R., Schwender, B., Volpe, T., Anderson, D.S., Mesquita- Fuentes, R., et al. (1997). Proteome studies of Saccharomyces cerevisiae: identification and characterization of abundant proteins. Electrophoresis 18, 1347-1360.   DOI
67 Gautschi, M., Just, S., Mun, A., Ross, S., Rucknagel, P., Dubaquie, Y., Ehrenhofer-Murray, A., and Rospert, S. (2003). The yeast N(alpha)-acetyltransferase NatA is quantitatively anchored to the ribosome and interacts with nascent polypeptides. Mol. Cell. Biol. 23, 7403-7414.   DOI
68 Gibbs, D.J., Lee, S.C., Isa, N.M., Gramuglia, S., Fukao, T., Bassel, G.W., Correia, C.S., Corbineau, F., Theodoulou, F.L., Bailey-Serres, J., et al. (2011). Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants. Nature 479, 415-418.   DOI
69 Ghislain, M., Dohmen, R.J., Levy, F., and Varshavsky, A. (1996). Cdc48p interacts with Ufd3p, a WD repeat protein required for ubiquitin-mediated proteolysis in Saccharomyces cerevisiae. EMBO J. 15, 4884-4899.
70 Gibbs, D.J. (2015). Emerging functions for N-terminal protein acetylation in plants. Trends Plant Sci. 20, 599-601.   DOI
71 Gibbs, D.J., Bacardit, J., Bachmair, A., and Holdsworth, M.J. (2014). The eukaryotic N-end rule pathway: conserved mechanisms and diverse functions. Trends Cell Biol. 24, 603-611.   DOI
72 Giglione, C., Vallon, O., and Meinnel, T. (2003). Control of protein life-span by N-terminal methionine excision. EMBO J. 22, 13-23.   DOI
73 Giglione, C., Fieulaine, S., and Meinnel, T. (2015). N-terminal protein modifications: bringing back into play the ribosome. Biochimie 114, 134-146.   DOI
74 Graveley, B.R., Brooks, A.N., Carlson, J.W., Duff, M.O., Landolin, J.M., Yang, L., Artieri, C.G., van Baren, M.J., Boley, N., Booth, B.W., et al. (2011). The developmental transcriptome of Drosophila melanogaster. Nature 471, 473-479.   DOI
75 Grimmer, J., Rodiger, A., Hoehenwarter, W., Helm, S., and Baginsky, S. (2014). The RNA-binding protein RNP29 is an unusual Toc159 transport substrate. Front Plant Sci. 5, 258.
76 Hershko, A., Heller, H., Eytan, E., Kaklij, G., and Rose, I.A. (1984). Role of the alpha-amino group of protein in ubiquitin-mediated protein breakdown. Proc. Natl. Acad. Sci. USA 81, 7021-7025.   DOI
77 Hammerle, M., Bauer, J., Rose, M., Szallies, A., Thumm, M., Dusterhus, S., Mecke, D., Entian, K.D., and Wolf, D.H. (1998). Proteins of newly isolated mutants and the amino-terminal proline are essential for ubiquitin-proteasome-catalyzed catabolite degradation of fructose-1,6-bisphosphatase of Saccharomyces cerevisiae. J. Biol. Chem. 273, 25000-25005.   DOI
78 Hassink, G., Kikkert, M., van Voorden, S., Lee, S.J., Spaapen, R., van Laar, T., Coleman, C.S., Bartee, E., Fruh, K., Chau, V., et al. (2005). TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. Biochem. J. 388, 647-655.   DOI
79 Helbig, A.O., Rosati, S., Pijnappel, P.W., Van Breukelen, B., Timmers, M.H., Mohammed, S., Slijper, M., and Heck, A.J. (2010). Perturbation of the yeast N-acetyltransferase NatB induces elevation of protein phosphorylation levels. BMC Genomics 11, 685.   DOI
80 Holmes, W.M., Mannakee, B.K., Gutenkunst, R.N., and Serio, T.R. (2014). Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding. Nat. Commun. 5, 4383.   DOI
81 Hu, R.G., Sheng, J., Qi, X., Xu, Z., Takahashi, T.T., and Varshavsky, A. (2005). The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. Nature 437, 981-986.   DOI
82 Hwang, C.S., Shemorry, A., Auerbach, D., and Varshavsky, A. (2010a). The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases. Nat. Cell Biol. 12, 1177-1185.   DOI
83 Kalvik, T.V., and Arnesen, T. (2013). Protein N-terminal acetyltransferases in cancer. Oncogene 32, 269-276.   DOI
84 Hwang, C.S., Shemorry, A., and Varshavsky, A. (2010b). N-terminal acetylation of cellular proteins creates specific degradation signals. Science 327, 973-977.   DOI
85 Hwang, C.S., Sukalo, M., Batygin, O., Addor, M.C., Brunner, H., Aytes, A.P., Mayerle, J., Song, H.K., Varshavsky, A., and Zenker, M. (2011). Ubiquitin ligases of the N-end rule pathway: assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome. PLoS One 6, e24925.   DOI
86 Jornvall, H. (1975). Acetylation of Protein N-terminal amino groups structural observations on alpha-amino acetylated proteins. J. Theoretic. Biol. 55, 1-12.   DOI
87 Kandoth, C., McLellan, M.D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J.F., Wyczalkowski, M.A., et al. (2013). Mutational landscape and significance across 12 major cancer types. Nature 502, 333-339.   DOI
88 Khmelinskii, A., and Knop, M. (2014). Analysis of protein dynamics with tandem fluorescent protein timers. Methods Mol. Biol. 1174, 195-210.   DOI
89 Kim, J.M., and Hwang, C.S. (2014). Crosstalk between the Arg/Nend and Ac/N-end rule. Cell Cycle 13, 1366-1367.   DOI
90 Kim, I., Miller, C.R., Young, D.L., and Fields, S. (2013). Highthroughput analysis of in vivo protein stability. Mol. Cell Proteomics 12, 3370-3378.   DOI
91 Kim, H.K., Kim, R.R., Oh, J.H., Cho, H., Varshavsky, A., and Hwang, C.S. (2014). The N-terminal methionine of cellular proteins as a degradation signal. Cell 156, 158-169.   DOI
92 Lee, J.H., Jiang, Y., Kwon, Y.T., and Lee, M.J. (2015). Pharmacological modulation of the N-End rule pathway and its therapeutic Implications. Trends Pharmacol. Sci. 36, 782-797.   DOI
93 Kwon, Y.T., Kashina, A.S., and Varshavsky, A. (1999). Alternative splicing results in differential expression, activity, and localization of the two forms of arginyl-tRNA-protein transferase, a component of the N-end rule pathway. Mol. Cell. Biol. 19, 182-193.   DOI
94 Lee, M.J., Tasaki, T., Moroi, K., An, J.Y., Kimura, S., Davydov, I.V., and Kwon, Y.T. (2005). RGS4 and RGS5 are in vivo substrates of the N-end rule pathway. Proc. Natl. Acad. Sci. USA 102, 15030-15035.   DOI
95 Lee, K.E., Ahn, J.Y., Kim, J.M., and Hwang, C.S. (2014). Synthetic lethal screen of NAA20, a catalytic subunit gene of NatB Nterminal acetylase in Saccharomyces cerevisiae. J. Microbiol. 52, 842-848.   DOI
96 Linster, E., Stephan, I., Bienvenut, W.V., Maple-Grodem, J., Myklebust, L.M., Huber, M., Reichelt, M., Sticht, C., Geir Moller, S., Meinnel, T., et al. (2015). Downregulation of N-terminal acetylation triggers ABA-mediated drought responses in Arabidopsis. Nat. Commun. 6, 7640.   DOI
97 Liu, C.M., Hsieh, C.L., He, Y.C., Lo, S.J., Liang, J.A., Hsieh, T.F., Josson, S., Chung, L.W., Hung, M.C., and Sung, S.Y. (2013). In vivo targeting of ADAM9 gene expression using lentivirusdelivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression. PLoS One 8, e53795.   DOI
98 Lu, Z., and Hunter, T. (2010). Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors. Cell Cycle 9, 2342-2352.   DOI
99 Malen, H., Lillehaug, J.R., and Arnesen, T. (2009). The protein Nalpha- terminal acetyltransferase hNaa10p (hArd1) is phosphorylated in HEK293 cells. BMC Res Notes 2, 32.   DOI
100 Ma, D.K., Vozdek, R., Bhatla, N., and Horvitz, H.R. (2012). CYSL-1 interacts with the O2-sensing hydroxylase EGL-9 to promote H2S-modulated hypoxia-induced behavioral plasticity in C. elegans. Neuron 73, 925-940.   DOI
101 Meinnel, T., Peynot, P., and Giglione, C. (2005). Processed Ntermini of mature proteins in higher eukaryotes and their major contribution to dynamic proteomics. Biochimie 87, 701-712.   DOI
102 Menssen, R., Schweiggert, J., Schreiner, J., Kusevic, D., Reuther, J., Braun, B., and Wolf, D.H. (2012). Exploring the topology of the Gid complex, the E3 ubiquitin ligase involved in cataboliteinduced degradation of gluconeogenic enzymes. J. Biol. Chem. 287, 25602-25614.   DOI
103 Mogk, A., and Bukau, B. (2010). Cell biology. When the beginning marks the end. Science 327, 966-967.   DOI
104 Mullen, J.R., Kayne, P.S., Moerschell, R.P., Tsunasawa, S., Gribskov, M., Colavito-Shepanski, M., Grunstein, M., Sherman, F., and Sternglanz, R. (1989). Identification and characterization of genes and mutants for an N-terminal acetyltransferase from yeast. EMBO J. 8, 2067-2075.
105 Narita, K. (1958). Isolation of acetylpeptide from enzymic digests of TMV-protein. Biochimi. Biophys. Acta 28, 184-191.   DOI
106 Park, E.C., and Szostak, J.W. (1992). ARD1 and NAT1 proteins form a complex that has N-terminal acetyltransferase activity. EMBO J. 11, 2087-2093.
107 Park, S.E., Kim, J.M., Seok, O.H., Cho, H., Wadas, B., Kim, S.Y., Varshavsky, A., and Hwang, C.S. (2015). Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway. Science 347, 1249-1252.   DOI