Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (3) : 258-270     DOI: 10.1007/s11684-016-0458-7
Physiological functions and clinical implications of the N-end rule pathway
Yujiao Liu1,2,Chao Liu2,3,Wen Dong1,*(),Wei Li2,*()
1. College of Marine Life, Ocean University of China, Qingdao 266003, China
2. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
3. University of Chinese Academy of Sciences, Beijing 100049, China
Download: PDF(428 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein’s half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradation signal of a protein and thus called N-degron. N-degron can be recognized and modifed by several steps of post-translational modifications, such as oxidation, deamination, arginylation or acetylation, it then polyubiquitinated by the N-recognin for degradation. The molecular basis of the N-end rule pathway has been elucidated and its physiological functions have been revealed in the past 30 years. This pathway is involved in several biological aspects, including transcription, differentiation, chromosomal segregation, genome stability, apoptosis, mitochondrial quality control, cardiovascular development, neurogenesis, carcinogenesis, and spermatogenesis. Disturbance of this pathway often causes the failure of these processes, resulting in some human diseases. This review summarized the physiological functions of the N-end rule pathway, introduced the related biological processes and diseases, with an emphasis on the inner link between this pathway and certain symptoms.

Keywords N-end rule pathway      Ate1      cardiovascular development      neurogenesis      spermatogenesis      neurodegenerative disorders      Johanson–Blizzard syndrome     
Corresponding Authors: Wen Dong,Wei Li   
Just Accepted Date: 05 July 2016   Online First Date: 04 August 2016    Issue Date: 30 August 2016
URL:     OR
Fig.1  Mammalian N-end rule pathway. (A) Mammalian Ac/N-end rule pathway. This pathway targets proteins through their Nα-terminally acetylated residues. The red arrow on the left indicates the co-translational removal of the initiator Met by Met-aminopeptidases (MetAPs). The N-terminal Met is retained when a residue at position 2 is larger than Val. (B) Mammalian Arg/N-end rule pathway. This pathway targets proteins for degradation through their specific unacetylated N-terminal residues. ATE1 is arginyl-tRNA-protein transferase. “Primary,” “secondary,” and “tertiary” refer to mechanistically distinct classes of destabilizing N-terminal residues. “Type I” and “Type II” refer to two sets of primary destabilizing N-terminal residues: basic and bulky hydrophobic, respectively.
Substrate Species N-degron Modifications References
RGS2 Homo sapiens/ Saccharomy cescerevisiae AcMQ-X Acetylation [30]
RGS4,5,16 Mus musculus RC*-X MetAPs cleavage, oxidation, arginylation [35,37]
REC8 Mus musculus E- X Separase cleavage,arginylation [53]
RIPK1TRAF1BRCA1EPHA4BIMELMETNEDD9LIMK1Lyn Mus musculusMus musculusMus musculusMus musculus Mus musculusMus musculus Homo sapiensHomo sapiensHomo sapiens C- XC- XD- XD- XR- XT- XT- XL- XL- X Caspase cleavage,oxidation Arginylation [54,55,116]
BIDBCLXLBakc-FosIkBaIgfbp2Capns1Atp2b2Capn1Ankrd2Grm1Ica512 Homo sapiens Mus musculus Mus musculus Mus musculus Mus musculus Mus musculus Mus musculus Mus musculus Homo sapiens Mus musculusMus musculusMus musculus R- XD- XE- XR- XE- XR- XD- XR- XL- XR- XT- XL- X Calpain cleavage, deamination, arginylation [55,73]
PINK1 Homo sapiens F-X Transmembrane signal cleavage by PARL [17]
APPTaua-synucleinTDP43 Homo sapiens D-XE-XQ-XR208-TDP43D219-TDP43D247-TDP43 Secretase, calpain, caspase, or MMP3 cleavage; deamination; arginylation (see details in main text “Cancers”) [16]
Tab.1  Representative substrates of the mammalian N-end rule pathway
Fig.2  Major biological function of the N-end rule pathway. The main biological functions of the N-end rule pathway include transcription through the degradation of IkBa and c-Fos, differentiation through the degradation of a growing factor Igfbp2, genome stability through the degradation of Scc1 and H2A, apoptosis through the degradation of a series of apoptotic proteins, mitochondrial quality control through the degradation of PINK, cardiovascular development through the degradation of RGS proteins, and spermatogenesis through the degradation of REC8.
Fig.3  Role of N-end rule pathway-mediated degradation of RGS proteins in cardiovascular development. G-protein coupled receptor (GPCR) transfers extracellular signals to the intracellular environment by dissolving heterotrimeric G-proteins and forming active Gα-GTP to stimulate downstream signal pathways. The RGS family acts as GTPase-activating proteins. As a result, the concentration of Gα-GTP in the cytosol decreases and downstream signaling is blocked.
Fig.4  Functional role of the N-end rule pathway in spermatogenesis. The N-end rule pathway participates in multiple stages of spermatogenesis. In prophase I, UBR1 facilitates the ubiquitination of H2A and H2B to maintain proper transcription and thus allow spermatocytes to bypass the pachytene checkpoint. In metaphase, the Ate1-mediated arginylation of the fragment of Rec8 cleaved by separase is required for its degradation. In spermiogenesis, histone replacement by protamine requires HR6B, which is the E2 of the N-end rule pathway.
1 Etlinger JD, Goldberg AL. A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proc Natl Acad Sci U S A 1977; 74(1): 54–58
doi: 10.1073/pnas.74.1.54 pmid: 264694
2 Schwartz AL, Ciechanover A. The ubiquitin-proteasome pathway and pathogenesis of human diseases. Annu Rev Med 1999; 50: 57–74
pmid: 10073263
3 Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002; 82(2): 373–428
doi: 10.1152/physrev.00027.2001 pmid: 11917093
4 Bedford L, Hay D, Paine S, Rezvani N, Mee M, Lowe J, Mayer RJ. Is malfunction of the ubiquitin proteasome system the primary cause of alpha-synucleinopathies and other chronic human neurodegenerative disease? Biochim Biophys Acta 2008; 1782(12): 683–690
doi: 10.1016/j.bbadis.2008.10.009 pmid: 18976704
5 Nedelsky NB, Todd PK, Taylor JP. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim Biophys Acta 2008; 1782(12): 691–699
doi: 10.1016/j.bbadis.2008.10.002 pmid: 18930136
6 Whatley BR, Li L, Chin LS. The ubiquitin-proteasome system in spongiform degenerative disorders. Biochim Biophys Acta 2008; 1782(12): 700–712
doi: 10.1016/j.bbadis.2008.08.006 pmid: 18790052
7 Murton AJ, Constantin D, Greenhaff PL. The involvement of the ubiquitin proteasome system in human skeletal muscle remodelling and atrophy. Biochim Biophys Acta 2008; 1782(12): 730–743
doi: 10.1016/j.bbadis.2008.10.011 pmid: 18992328
8 Mearini G, Schlossarek S, Willis MS, Carrier L. The ubiquitin-proteasome system in cardiac dysfunction. Biochim Biophys Acta 2008; 1782(12): 749–763
doi: 10.1016/j.bbadis.2008.06.009 pmid: 18634872
9 Rajan V, Mitch WE. Ubiquitin, proteasomes and proteolytic mechanisms activated by kidney disease. Biochim Biophys Acta 2008; 1782(12): 795–799
doi: 10.1016/j.bbadis.2008.07.007 pmid: 18723090
10 Voutsadakis IA. The ubiquitin-proteasome system in colorectal cancer. Biochim Biophys Acta 2008; 1782(12): 800–808
doi: 10.1016/j.bbadis.2008.06.007 pmid: 18619533
11 Varshavsky A. The N-end rule pathway and regulation by proteolysis. Protein Sci 2011; 20(8): 1298–1345
doi: 10.1002/pro.666 pmid: 21633985
12 Sriram SM, Kim BY, Kwon YT. The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat Rev Mol Cell Biol 2011; 12(11): 735–747
doi: 10.1038/nrm3217 pmid: 22016057
13 Bachmair A, Finley D, Varshavsky A. In vivo half-life of a protein is a function of its amino-terminal residue. Science 1986; 234(4773): 179–186
doi: 10.1126/science.3018930 pmid: 3018930
14 Varshavsky A. The ubiquitin system, an immense realm. Annu Rev Biochem 2012; 81: 167–176
pmid: 22663079
15 Ellery KM, Erdman SH. Johanson‒Blizzard syndrome: expanding the phenotype of exocrine pancreatic insufficiency. JOP 2014; 15(4): 388–390
pmid: 25076350
16 Brower CS, Piatkov KI, Varshavsky A. Neurodegeneration-associated protein fragments as short-lived substrates of the N-end rule pathway. Mol Cell 2013; 50(2): 161–171
doi: 10.1016/j.molcel.2013.02.009 pmid: 23499006
17 Yamano K, Youle RJ. PINK1 is degraded through the N-end rule pathway. Autophagy 2013; 9(11): 1758–1769
doi: 10.4161/auto.24633 pmid: 24121706
18 Atik T, Karakoyun M, Sukalo M, Zenker M, Ozkinay F, Aydoğdu S. Two novel UBR1 gene mutations in a patient with Johanson Blizzard Syndrome: a mild phenotype without mental retardation. Gene 2015; 570(1): 153–155
doi: 10.1016/j.gene.2015.06.082 pmid: 26149651
19 Dougan DA, Micevski D, Truscott KN. The N-end rule pathway: from recognition by N-recognins to destruction by AAA+ proteases. Biochim Biophys Acta. 2012; 1823(1):83–91
doi: 10.1016/j.bbamcr.2011.07.002 PMID:21781991
20 Gibbs DJ, Bacardit J, Bachmair A, Holdsworth MJ. The eukaryotic N-end rule pathway: conserved mechanisms and diverse functions. Trends Cell Biol 2014; 24(10): 603–611
pmid: 24874449
21 Hwang CS, Shemorry A, Auerbach D, Varshavsky A. The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases. Nat Cell Biol 2010; 12(12): 1177–1185
pmid: 21076411
22 Kim HK, Kim RR, Oh JH, Cho H, Varshavsky A, Hwang CS. The N-terminal methionine of cellular proteins as a degradation signal. Cell 2014; 156(1-2): 158–169
pmid: 24361105
23 Tasaki T, Sriram SM, Park KS, Kwon YT. The N-end rule pathway. Annu Rev Biochem 2012; 81: 261–289
pmid: 22524314
24 Bachmair A, Varshavsky A. The degradation signal in a short-lived protein. Cell 1989; 56(6): 1019–1032
doi: 10.1016/0092-8674(89)90635-1 pmid: 2538246
25 Prakash S, Tian L, Ratliff KS, Lehotzky RE, Matouschek A. An unstructured initiation site is required for efficient proteasome-mediated degradation. Nat Struct Mol Biol 2004; 11(9): 830–837
doi: 10.1038/nsmb814 pmid: 15311270
26 Suzuki T, Varshavsky A. Degradation signals in the lysine-asparagine sequence space. EMBO J 1999; 18(21): 6017–6026
doi: 10.1093/emboj/18.21.6017 pmid: 10545113
27 Hwang CS, Shemorry A, Varshavsky A. N-terminal acetylation of cellular proteins creates specific degradation signals. Science 2010; 327(5968): 973–977
doi: 10.1126/science.1183147 pmid: 20110468
28 Shemorry A, Hwang CS, Varshavsky A. Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway. Mol Cell 2013; 50(4): 540–551
doi: 10.1016/j.molcel.2013.03.018 pmid: 23603116
29 Frottin F, Martinez A, Peynot P, Mitra S, Holz RC, Giglione C, Meinnel T. The proteomics of N-terminal methionine cleavage. Mol Cell Proteomics 2006; 5(12): 2336–2349
doi: 10.1074/mcp.M600225-MCP200 pmid: 16963780
30 Park SE, Kim JM, Seok OH, Cho H, Wadas B, Kim SY, Varshavsky A, Hwang CS. Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway. Science 2015; 347(6227): 1249–1252
doi: 10.1126/science.aaa3844 pmid: 25766235
31 Grigoryev S, Stewart AE, Kwon YT, Arfin SM, Bradshaw RA, Jenkins NA, Copeland NG, Varshavsky A. A mouse amidase specific for N-terminal asparagine. The gene, the enzyme, and their function in the N-end rule pathway. J Biol Chem 1996; 271(45): 28521–28532
doi: 10.1074/jbc.271.45.28521 pmid: 8910481
32 Kwon YT, Balogh SA, Davydov IV, Kashina AS, Yoon JK, Xie Y, Gaur A, Hyde L, Denenberg VH, Varshavsky A. Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway. Mol Cell Biol 2000; 20(11): 4135–4148
doi: 10.1128/MCB.20.11.4135-4148.2000 pmid: 10805755
33 Wang H, Piatkov KI, Brower CS, Varshavsky A. Glutamine-specific N-terminal amidase, a component of the N-end rule pathway. Mol Cell 2009; 34(6): 686–695
doi: 10.1016/j.molcel.2009.04.032 pmid: 19560421
34 Lee KE, Heo JE, Kim JM, Hwang CS. N-terminal acetylation-targeted N-end rule proteolytic system: the Ac/N-end rule pathway. Mol Cells 2016; 39(3): 169–178
doi: 10.14348/molcells.2016.2329 pmid: 26883906
35 Hu RG, Sheng J, Qi X, Xu Z, Takahashi TT, Varshavsky A. The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. Nature 2005; 437(7061): 981–986
doi: 10.1038/nature04027 pmid: 16222293
36 Kwon YT, Kashina AS, Davydov IV, Hu RG, An JY, Seo JW, Du F, Varshavsky A. An essential role of N-terminal arginylation in cardiovascular development. Science 2002; 297(5578): 96–99
doi: 10.1126/science.1069531 pmid: 12098698
37 Lee MJ, Tasaki T, Moroi K, An JY, Kimura S, Davydov IV, Kwon YT. RGS4 and RGS5 are in vivo substrates of the N-end rule pathway. Proc Natl Acad Sci U S A 2005; 102(42): 15030–15035
doi: 10.1073/pnas.0507533102 pmid: 16217033
38 Balzi E, Choder M, Chen WN, Varshavsky A, Goffeau A. Cloning and functional analysis of the arginyl-tRNA-protein transferase gene ATE1 of Saccharomyces cerevisiae. J Biol Chem 1990; 265(13): 7464–7471
pmid: 2185248
39 Li J, Pickart CM. Binding of phenylarsenoxide to Arg-tRNA protein transferase is independent of vicinal thiols. Biochemistry 1995; 34(48): 15829–15837
doi: 10.1021/bi00048a028 pmid: 7495814
40 Varshavsky A. The N-end rule: functions, mysteries, uses. Proc Natl Acad Sci U S A 1996; 93(22): 12142–12149
doi: 10.1073/pnas.93.22.12142 pmid: 8901547
41 Tasaki T, Zakrzewska A, Dudgeon DD, Jiang Y, Lazo JS, Kwon YT. The substrate recognition domains of the N-end rule pathway. J Biol Chem 2009; 284(3): 1884–1895
doi: 10.1074/jbc.M803641200 pmid: 19008229
42 Tasaki T, Kwon YT. The mammalian N-end rule pathway: new insights into its components and physiological roles. Trends Biochem Sci 2007; 32(11): 520–528
doi: 10.1016/j.tibs.2007.08.010 pmid: 17962019
43 Mogk A, Schmidt R, Bukau B. The N-end rule pathway for regulated proteolysis: prokaryotic and eukaryotic strategies. Trends Cell Biol 2007; 17(4): 165–172
doi: 10.1016/j.tcb.2007.02.001 pmid: 17306546
44 Starheim KK, Gevaert K, Arnesen T. Protein N-terminal acetyltransferases: when the start matters. Trends Biochem Sci 2012; 37(4): 152–161
doi: 10.1016/j.tibs.2012.02.003 pmid: 22405572
45 Van Damme P, Hole K, Pimenta-Marques A, Helsens K, Vandekerckhove J, Martinho RG, Gevaert K, Arnesen T. NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation. PLoS Genet 2011; 7(7): e1002169
doi: 10.1371/journal.pgen.1002169 pmid: 21750686
46 Johnson ES, Bartel B, Seufert W, Varshavsky A. Ubiquitin as a degradation signal. EMBO J 1992; 11(2): 497–505
pmid: 1311250
47 Johnson ES, Ma PC, Ota IM, Varshavsky A. A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem 1995; 270(29): 17442–17456
doi: 10.1074/jbc.270.29.17442 pmid: 7615550
48 Arfin SM, Bradshaw RA. Cotranslational processing and protein turnover in eukaryotic cells. Biochemistry 1988; 27(21): 7979–7984
doi: 10.1021/bi00421a001 pmid: 3069123
49 Kendall RL, Bradshaw RA. Isolation and characterization of the methionine aminopeptidase from porcine liver responsible for the co-translational processing of proteins. J Biol Chem 1992; 267(29): 20667–20673
pmid: 1328207
50 Rao H, Uhlmann F, Nasmyth K, Varshavsky A. Degradation of a cohesin subunit by the N-end rule pathway is essential for chromosome stability. Nature 2001; 410(6831): 955–959
doi: 10.1038/35073627 pmid: 11309624
51 Uhlmann F, Lottspeich F, Nasmyth K. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 1999; 400(6739): 37–42
doi: 10.1038/21831 pmid: 10403247
52 Hauf S, Waizenegger IC, Peters JM. Cohesin cleavage by separase required for anaphase and cytokinesis in human cells. Science 2001; 293(5533): 1320–1323
doi: 10.1126/science.1061376 pmid: 11509732
53 Liu YJ, Liu C, Chang Z, Wadas B, Brower CS, Song ZH, Xu ZL, Shang YL, Liu WX, Wang LN, Dong W, Varshavsky A, Hu RG, Li W. Degradation of the separase-cleaved Rec8, a meiotic cohesin subunit, by the N-end rule pathway. J Biol Chem 2016; 291(14): 7426–7438
doi: 10.1074/jbc.M116.714964 pmid: 26858254
54 Xu Z, Payoe R, Fahlman RP. 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 2012; 287(10): 7495–7502
doi: 10.1074/jbc.M111.301002 pmid: 22262859
55 Piatkov KI, Brower CS, Varshavsky A. The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments. Proc Natl Acad Sci U S A 2012; 109(27): E1839–E1847
doi: 10.1073/pnas.1207786109 pmid: 22670058
56 Gavel Y, von Heijne G. Cleavage-site motifs in mitochondrial targeting peptides. Protein Eng 1990; 4(1): 33–37
doi: 10.1093/protein/4.1.33 pmid: 2290832
57 Neupert W, Herrmann JM. Translocation of proteins into mitochondria. Annu Rev Biochem 2007; 76: 723–749
pmid: 17263664
58 Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 2010; 191(5): 933–942
doi: 10.1083/jcb.201008084 pmid: 21115803
59 Shi G, Lee JR, Grimes DA, Racacho L, Ye D, Yang H, Ross OA, Farrer M, McQuibban GA, Bulman DE. Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson’s disease. Hum Mol Genet 2011; 20(10): 1966–1974
doi: 10.1093/hmg/ddr077 pmid: 21355049
60 Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, McBride HM, Park DS, Fon EA. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep 2012; 13(4): 378–385
doi: 10.1038/embor.2012.14 pmid: 22354088
61 Hennessey ES, Drummond DR, Sparrow JC. Post-translational processing of the amino terminus affects actin function. Eur J Biochem 1991; 197(2): 345–352
doi: 10.1111/j.1432-1033.1991.tb15917.x pmid: 1902786
62 Sheff DR, Rubenstein PA. Identification of N-acetylmethionine as the product released during the NH2-terminal processing of a pseudo-class I actin. J Biol Chem 1989; 264(19): 11491–11496
pmid: 2738074
63 Karakozova M, Kozak M, Wong CC, Bailey AO, Yates JR 3rd, Mogilner A, Zebroski H, Kashina A. Arginylation of β-actin regulates actin cytoskeleton and cell motility. Science 2006; 313(5784): 192–196
doi: 10.1126/science.1129344 pmid: 16794040
64 Hu RG, Wang H, Xia Z, Varshavsky A. The N-end rule pathway is a sensor of heme. Proc Natl Acad Sci U S A 2008; 105(1): 76–81
doi: 10.1073/pnas.0710568105 pmid: 18162538
65 Eisele F, Wolf DH. Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS Lett 2008; 582(30): 4143–4146
doi: 10.1016/j.febslet.2008.11.015 pmid: 19041308
66 Sultana R, Theodoraki MA, Caplan AJ. UBR1 promotes protein kinase quality control and sensitizes cells to Hsp90 inhibition. Exp Cell Res 2012; 318(1): 53–60
doi: 10.1016/j.yexcr.2011.09.010 pmid: 21983172
67 Hwang CS, Shemorry A, Varshavsky A. Two proteolytic pathways regulate DNA repair by cotargeting the Mgt1 alkylguanine transferase. Proc Natl Acad Sci U S A 2009; 106(7): 2142–2147
doi: 10.1073/pnas.0812316106 pmid: 19164530
68 Hwang CS, Shemorry A, Auerbach D, Varshavsky A. The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases. Nat Cell Biol 2010; 12(12): 1177–1185
doi: 10.1038/ncb2121 pmid: 21076411
69 Byrd C, Turner GC, Varshavsky A. The N-end rule pathway controls the import of peptides through degradation of a transcriptional repressor. EMBO J 1998; 17(1): 269–277
doi: 10.1093/emboj/17.1.269 pmid: 9427760
70 Xia Z, Turner GC, Hwang CS, Byrd C, Varshavsky A. Amino acids induce peptide uptake via accelerated degradation of CUP9, the transcriptional repressor of the PTR2 peptide transporter. J Biol Chem 2008; 283(43): 28958–28968
doi: 10.1074/jbc.M803980200 pmid: 18708352
71 Graciet E, Wellmer F. The plant N-end rule pathway: structure and functions. Trends Plant Sci 2010; 15(8): 447–453
doi: 10.1016/j.tplants.2010.04.011 pmid: 20627801
72 Zhang H, Deery MJ, Gannon L, Powers SJ, Lilley KS, Theodoulou FL. Quantitative proteomics analysis of the Arg/N-end rule pathway of targeted degradation in Arabidopsis roots. Proteomics 2015; 15(14): 2447–2457
doi: 10.1002/pmic.201400530 pmid: 25728785
73 Piatkov KI, Oh JH, Liu Y, Varshavsky A. Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway. Proc Natl Acad Sci U S A 2014; 111(9): E817–E826
doi: 10.1073/pnas.1401639111 pmid: 24550490
74 Brower CS, Varshavsky A. Ablation of arginylation in the mouse N-end rule pathway: loss of fat, higher metabolic rate, damaged spermatogenesis, and neurological perturbations. PLoS One 2009; 4(11): e7757
doi: 10.1371/journal.pone.0007757 pmid: 19915679
75 Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, Beier M, Hülskamp G, Guzman C, Rehder H, Beemer FA, Hamel B, Vanlieferinghen P, Gershoni-Baruch R, Vieira MW, Dumic M, Auslender R, Gil-da-Silva-Lopes VL, Steinlicht S, Rauh M, Shalev SA, Thiel C, Ekici AB, Winterpacht A, Kwon YT, Varshavsky A, Reis A. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson‒Blizzard syndrome). Nat Genet 2005; 37(12): 1345–1350
doi: 10.1038/ng1681 pmid: 16311597
76 Dolatshad NF, Hellen N, Jabbour RJ, Harding SE, Földes G. G-protein coupled receptor signaling in pluripotent stem cell-derived cardiovascular cells: implications for disease modeling. Front Cell Dev Biol 2015; 3: 76 PMID:26697426
77 Branco AF, Allen BG. G protein-coupled receptor signaling in cardiac nuclear membranes. J Cardiovasc Pharmacol 2015; 65(2): 101–109
doi: 10.1097/FJC.0000000000000196 pmid: 25658310
78 Sato PY, Chuprun JK, Schwartz M, Koch WJ. The evolving impact of G protein-coupled receptor kinases in cardiac health and disease. Physiol Rev 2015; 95(2): 377–404
doi: 10.1152/physrev.00015.2014 pmid: 25834229
79 Tamirisa P, Blumer KJ, Muslin AJ. RGS4 inhibits G-protein signaling in cardiomyocytes. Circulation 1999; 99(3): 441–447
doi: 10.1161/01.CIR.99.3.441 pmid: 9918533
80 Lee MJ, Kim DE, Zakrzewska A, Yoo YD, Kim SH, Kim ST, Seo JW, Lee YS, Dorn GW 2nd, Oh U, Kim BY, Kwon YT. Characterization of arginylation branch of N-end rule pathway in G-protein-mediated proliferation and signaling of cardiomyocytes. J Biol Chem 2012; 287(28): 24043–24052
doi: 10.1074/jbc.M112.364117 pmid: 22577142
81 An JY, Seo JW, Tasaki T, Lee MJ, Varshavsky A, Kwon YT. Impaired neurogenesis and cardiovascular development in mice lacking the E3 ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Proc Natl Acad Sci U S A 2006; 103(16): 6212–6217
doi: 10.1073/pnas.0601700103 pmid: 16606826
82 Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH, Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ, Steinberg TH, Wyss JM, Mecham RP, Blumer KJ. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest 2003; 111(4): 445–452
doi: 10.1172/JCI15598 pmid: 12588882
83 Kimple AJ, Bosch DE, Giguère PM, Siderovski DP. Regulators of G-protein signaling and their Ga substrates: promises and challenges in their use as drug discovery targets. Pharmacol Rev 2011; 63(3): 728–749
doi: 10.1124/pr.110.003038 pmid: 21737532
84 Nance MR, Kreutz B, Tesmer VM, Sterne-Marr R, Kozasa T, Tesmer JJ. Structural and functional analysis of the regulator of G protein signaling 2-gaq complex. Structure 2013; 21(3): 438–448
doi: 10.1016/j.str.2012.12.016 pmid: 23434405
85 Yang J, Kamide K, Kokubo Y, Takiuchi S, Tanaka C, Banno M, Miwa Y, Yoshii M, Horio T, Okayama A, Tomoike H, Kawano Y, Miyata T. Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population. J Hypertens 2005; 23(8): 1497–1505
doi: 10.1097/ pmid: 16003176
86 Kurosaka S, Leu NA, Pavlov I, Han X, Ribeiro PA, Xu T, Bunte R, Saha S, Wang J, Cornachione A, Mai W, Yates JR 3rd, Rassier DE, Kashina A. Arginylation regulates myofibrils to maintain heart function and prevent dilated cardiomyopathy. J Mol Cell Cardiol 2012; 53(3): 333–341
doi: 10.1016/j.yjmcc.2012.05.007 pmid: 22626847
87 Götz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol 2005; 6(10): 777–788
doi: 10.1038/nrm1739 pmid: 16314867
88 Petronczki M, Siomos MF, Nasmyth K. Un ménage à quatre: the molecular biology of chromosome segregation in meiosis. Cell 2003; 112(4): 423–440
doi: 10.1016/S0092-8674(03)00083-7 pmid: 12600308
89 Zickler D, Kleckner N. Recombination, pairing, and synapsis of homologs during meiosis. Cold Spring Harb Perspect Biol 2015; 7(6): a016626
doi: 10.1101/cshperspect.a016626 pmid: 25986558
90 Kudo NR, Wassmann K, Anger M, Schuh M, Wirth KG, Xu H, Helmhart W, Kudo H, McKay M, Maro B, Ellenberg J, de Boer P, Nasmyth K. Resolution of chiasmata in oocytes requires separase-mediated proteolysis. Cell 2006; 126(1): 135–146
doi: 10.1016/j.cell.2006.05.033 pmid: 16839882
91 Nasmyth K, Haering CH. The structure and function of SMC and kleisin complexes. Annu Rev Biochem 2005; 74: 595–648
pmid: 15952899
92 Kwon YT, Xia Z, Davydov IV, Lecker SH, Varshavsky A. Construction and analysis of mouse strains lacking the ubiquitin ligase UBR1 (E3α) of the N-end rule pathway. Mol Cell Biol 2001; 21(23): 8007–8021
doi: 10.1128/MCB.21.23.8007-8021.2001 pmid: 11689692
93 Kwon YT, Xia Z, An JY, Tasaki T, Davydov IV, Seo JW, Sheng J, Xie Y, Varshavsky A. Female lethality and apoptosis of spermatocytes in mice lacking the UBR2 ubiquitin ligase of the N-end rule pathway. Mol Cell Biol 2003; 23(22): 8255–8271
doi: 10.1128/MCB.23.22.8255-8271.2003 pmid: 14585983
94 An JY, Kim E, Zakrzewska A, Yoo YD, Jang JM, Han DH, Lee MJ, Seo JW, Lee YJ, Kim TY, de Rooij DG, Kim BY, Kwon YT. UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells. PLoS One 2012; 7(5): e37414
doi: 10.1371/journal.pone.0037414 pmid: 22616001
95 An JY, Kim EA, Jiang Y, Zakrzewska A, Kim DE, Lee MJ, Mook-Jung I, Zhang Y, Kwon YT. UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination. Proc Natl Acad Sci U S A 2010; 107(5): 1912–1917
doi: 10.1073/pnas.0910267107 pmid: 20080676
96 Turner JM, Mahadevaiah SK, Fernandez-Capetillo O, Nussenzweig A, Xu X, Deng CX, Burgoyne PS. Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet 2005; 37(1): 41–47
pmid: 15580272
97 Schimenti J. Synapsis or silence. Nat Genet 2005; 37(1): 11–13
doi: 10.1038/ng0105-11 pmid: 15624015
98 Handel MA. The XY body: a specialized meiotic chromatin domain. Exp Cell Res 2004; 296(1): 57–63
doi: 10.1016/j.yexcr.2004.03.008 pmid: 15120994
99 Monesi V. Differential rate of ribonucleic acid synthesis in the autosomes and sex chromosomes during male meiosis in the mouse. Chromosoma 1965; 17(1): 11–21
doi: 10.1007/BF00285153 pmid: 5833946
100 Turner JM. Meiotic sex chromosome inactivation. Development 2007; 134(10): 1823–1831
doi: 10.1242/dev.000018 pmid: 17329371
101 Cloutier JM, Turner JM. Meiotic sex chromosome inactivation. Curr Biol 2010; 20(22): R962–R963
doi: 10.1016/j.cub.2010.09.041 pmid: 21093783
102 Roest HP, van Klaveren J, de Wit J, van Gurp CG, Koken MH, Vermey M, van Roijen JH, Hoogerbrugge JW, Vreeburg JT, Baarends WM, Bootsma D, Grootegoed JA, Hoeijmakers JH. Inactivation of the HR6B ubiquitin-conjugating DNA repair enzyme in mice causes male sterility associated with chromatin modification. Cell 1996; 86(5): 799–810
doi: 10.1016/S0092-8674(00)80154-3 pmid: 8797826
103 Buonomo SB, Clyne RK, Fuchs J, Loidl J, Uhlmann F, Nasmyth K. Disjunction of homologous chromosomes in meiosis I depends on proteolytic cleavage of the meiotic cohesin Rec8 by separin. Cell 2000; 103(3): 387–398
doi: 10.1016/S0092-8674(00)00131-8 pmid: 11081626
104 Kitajima TS, Miyazaki Y, Yamamoto M, Watanabe Y. Rec8 cleavage by separase is required for meiotic nuclear divisions in fission yeast. EMBO J 2003; 22(20): 5643–5653
doi: 10.1093/emboj/cdg527 pmid: 14532136
105 Uhlmann F, Wernic D, Poupart MA, Koonin EV, Nasmyth K. Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast. Cell 2000; 103(3): 375–386
doi: 10.1016/S0092-8674(00)00130-6 pmid: 11081625
106 Waizenegger IC, Hauf S, Meinke A, Peters JM. Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell 2000; 103(3): 399–410
doi: 10.1016/S0092-8674(00)00132-X pmid: 11081627
107 Johanson A, Blizzard R. A syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr 1971; 79(6): 982–987
doi: 10.1016/S0022-3476(71)80194-4 pmid: 5171616
108 Sukalo M, Fiedler A, Guzmán C, Spranger S, Addor MC, McHeik JN, Oltra Benavent M, Cobben JM, Gillis LA, Shealy AG, Deshpande C, Bozorgmehr B, Everman DB, Stattin EL, Liebelt J, Keller KM, Bertola DR, van Karnebeek CDM, Bergmann C, Liu Z, Düker G, Rezaei N, Alkuraya FS, Oğur G, Alrajoudi A, Venegas-Vega CA, Verbeek NE, Richmond EJ, Kirbiyik O, Ranganath P, Singh A, Godbole K, Ali FAM, Alves C, Mayerle J, Lerch MM, Witt H, Zenker M. Mutations in the human UBR1 gene and the associated phenotypic spectrum. Hum Mutat 2014; 35(5): 521–531
doi: 10.1002/humu.22538 pmid: 24599544
109 Quaio CR, Koda YK, Bertola DR, Sukalo M, Zenker M, Kim CA. Johanson‒Blizzard syndrome: a report of gender-discordant twins with a novel UBR1 mutation. Genet Mol Res 2014; 13(2): 4159–4164 PMID:25036160
doi: 10.4238/2014.June.9.2
110 Hwang CS, Sukalo M, Batygin O, Addor MC, Brunner H, Aytes AP, Mayerle J, Song HK, Varshavsky A, Zenker M. Ubiquitin ligases of the N-end rule pathway: assessment of mutations in UBR1 that cause the Johanson‒Blizzard syndrome. PLoS One 2011; 6(9): e24925
doi: 10.1371/journal.pone.0024925 pmid: 21931868
111 Quintás-Cardama A, Kantarjian H, Cortes J. Imatinib and beyond — exploring the full potential of targeted therapy for CML. Nat Rev Clin Oncol 2009; 6(9): 535–543
doi: 10.1038/nrclinonc.2009.112 pmid: 19652654
112 Eldeeb MA, Fahlman RP. The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway. Oncotarget 2014; 5(9): 2714–2722
doi: 10.18632/oncotarget.1931 pmid: 24798867
113 Hayette S, Chabane K, Michallet M, Michallat E, Cony-Makhoul P, Salesse S, Maguer-Satta V, Magaud JP, Nicolini FE. Longitudinal studies of SRC family kinases in imatinib- and dasatinib-resistant chronic myelogenous leukemia patients. Leuk Res 2011; 35(1): 38–43
doi: 10.1016/j.leukres.2010.06.030 pmid: 20673586
114 Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, Talpaz M. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101(2): 690–698
doi: 10.1182/blood.V101.2.690 pmid: 12509383
115 Luciano F, Herrant M, Jacquel A, Ricci JE, Auberger P. The p54 cleaved form of the tyrosine kinase Lyn generated by caspases during BCR-induced cell death in B lymphoma acts as a negative regulator of apoptosis. FASEB J 2003; 17(6): 711–713
pmid: 12586738
116 Gamas P, Marchetti S, Puissant A, Grosso S, Jacquel A, Colosetti P, Pasquet JM, Mahon FX, Cassuto JP, Auberger P. Inhibition of imatinib-mediated apoptosis by the caspase-cleaved form of the tyrosine kinase Lyn in chronic myelogenous leukemia cells. Leukemia 2009; 23(8): 1500–1506
doi: 10.1038/leu.2009.60 pmid: 19340007
117 Luciano F, Ricci JE, Auberger P. Cleavage of Fyn and Lyn in their N-terminal unique regions during induction of apoptosis: a new mechanism for Src kinase regulation. Oncogene 2001; 20(36): 4935–4941
doi: 10.1038/sj.onc.1204661 pmid: 11526478
118 Chen E, Kwon YT, Lim MS, Dubé ID, Hough MR. Loss of Ubr1 promotes aneuploidy and accelerates B-cell lymphomagenesis in TLX1/HOX11-transgenic mice. Oncogene 2006; 25(42): 5752–5763
doi: 10.1038/sj.onc.1209573 pmid: 16862188
119 Yin J, Kwon YT, Varshavsky A, Wang W. RECQL4, mutated in the Rothmund‒Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Hum Mol Genet 2004; 13(20): 2421–2430
doi: 10.1093/hmg/ddh269 pmid: 15317757
120 Kwak KS, Zhou X, Solomon V, Baracos VE, Davis J, Bannon AW, Boyle WJ, Lacey DL, Han HQ. Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3α-II during cancer cachexia. Cancer Res 2004; 64(22): 8193–8198
doi: 10.1158/0008-5472.CAN-04-2102 pmid: 15548684
121 Rai R, Zhang F, Colavita K, Leu NA, Kurosaka S, Kumar A, Birnbaum MD, Győrffy B, Dong DW, Shtutman M, Kashina A. Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers. Oncogene 2015 Dec 21. [Epub ahead of print] PMID:26686093
doi: 10.1038/onc.2015.473
122 Eisenberg D, Jucker M. The amyloid state of proteins in human diseases. Cell 2012; 148(6): 1188–1203
doi: 10.1016/j.cell.2012.02.022 pmid: 22424229
123 Lindquist SL, Kelly JW. Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis. Cold Spring Harb Perspect Biol 2011; 3(12): a004507
doi: 10.1101/cshperspect.a004507 pmid: 21900404
124 Selkoe DJ. Alzheimer’s disease. Cold Spring Harb Perspect Biol 2011; 3(7): a004457
doi: 10.1101/cshperspect.a004457 pmid: 21576255
125 Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012; 148(6): 1204–1222
doi: 10.1016/j.cell.2012.02.040 pmid: 22424230
126 Garg S, Timm T, Mandelkow EM, Mandelkow E, Wang Y. Cleavage of Tau by calpain in Alzheimer’s disease: the quest for the toxic 17 kD fragment. Neurobiol Aging 2011; 32(1): 1–14
doi: 10.1016/j.neurobiolaging.2010.09.008 pmid: 20961659
127 Zilka N, Kovacech B, Barath P, Kontsekova E, Novák M. The self-perpetuating tau truncation circle. Biochem Soc Trans 2012; 40(4): 681–686
doi: 10.1042/BST20120015 pmid: 22817716
128 Rochet JC, Hay BA, Guo M. Molecular insights into Parkinson’s disease. Prog Mol Biol Transl Sci 2012; 107: 125–188
pmid: 22482450
129 Cremades N, Cohen SI, Deas E, Abramov AY, Chen AY, Orte A, Sandal M, Clarke RW, Dunne P, Aprile FA, Bertoncini CW, Wood NW, Knowles TP, Dobson CM, Klenerman D. Direct observation of the interconversion of normal and toxic forms of a-synuclein. Cell 2012; 149(5): 1048–1059
doi: 10.1016/j.cell.2012.03.037 pmid: 22632969
130 Choi DH, Kim YJ, Kim YG, Joh TH, Beal MF, Kim YS. Role of matrix metalloproteinase 3-mediated α-synuclein cleavage in dopaminergic cell death. J Biol Chem 2011; 286(16): 14168–14177
doi: 10.1074/jbc.M111.222430 pmid: 21330369
131 Levin J, Giese A, Boetzel K, Israel L, Högen T, Nübling G, Kretzschmar H, Lorenzl S. Increased alpha-synuclein aggregation following limited cleavage by certain matrix metalloproteinases. Exp Neurol 2009; 215(1): 201–208
doi: 10.1016/j.expneurol.2008.10.010 pmid: 19022250
132 Lee EB, Lee VM, Trojanowski JQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 2012; 13(1): 38–50
pmid: 22127299
133 Igaz LM, Kwong LK, Chen-Plotkin A, Winton MJ, Unger TL, Xu Y, Neumann M, Trojanowski JQ, Lee VM. Expression of TDP-43 C-terminal fragments in vitro recapitulates pathological features of TDP-43 proteinopathies. J Biol Chem 2009; 284(13): 8516–8524
doi: 10.1074/jbc.M809462200 pmid: 19164285
134 Nonaka T, Kametani F, Arai T, Akiyama H, Hasegawa M. Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. Hum Mol Genet 2009; 18(18): 3353–3364
doi: 10.1093/hmg/ddp275 pmid: 19515851
135 Pesiridis GS, Tripathy K, Tanik S, Trojanowski JQ, Lee VM. A “two-hit” hypothesis for inclusion formation by carboxyl-terminal fragments of TDP-43 protein linked to RNA depletion and impaired microtubule-dependent transport. J Biol Chem 2011; 286(21): 18845–18855
doi: 10.1074/jbc.M111.231118 pmid: 21454607
136 Palomo GM, Manfredi G. Exploring new pathways of neurodegeneration in ALS: the role of mitochondria quality control. Brain Res 2015; 1607: 36–46
pmid: 25301687
137 Schon EA, Przedborski S. Mitochondria: the next (neurode)generation. Neuron 2011; 70(6): 1033–1053
doi: 10.1016/j.neuron.2011.06.003 pmid: 21689593
138 Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010; 8(1): e1000298
doi: 10.1371/journal.pbio.1000298 pmid: 20126261
139 Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, May J, Tocilescu MA, Liu W, Ko HS, Magrané J, Moore DJ, Dawson VL, Grailhe R, Dawson TM, Li C, Tieu K, Przedborski S. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 2010; 107(1): 378–383
doi: 10.1073/pnas.0911187107 pmid: 19966284
140 Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183(5): 795–803
doi: 10.1083/jcb.200809125 pmid: 19029340
141 Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006; 441(7097): 1157–1161
doi: 10.1038/nature04788 pmid: 16672980
142 Kwon YT, Lévy F, Varshavsky A. Bivalent inhibitor of the N-end rule pathway. J Biol Chem 1999; 274(25): 18135–18139
doi: 10.1074/jbc.274.25.18135 pmid: 10364269
[1] Raafat Hegazy,Abdelmonem Hegazy,Mustafa Ammar,Emad Salem. Immunohistochemical measurement and expression of Mcl-1 in infertile testes[J]. Front. Med., 2015, 9(3): 361-367.
Full text