泛素化修饰与身体调控及疾病的关系(3)
来源：学术堂 作者：朱老师
发布于：2017-04-12 共13341字
神经退行性疾病如帕金森或阿尔兹海默氏病又或者多聚谷氨酰胺重复疾病如亨廷顿氏病都以蛋白质聚集体的毒性累积为特征，从而破坏细胞稳态与神经元功能而致病。而尽管不同疾病中蛋白质聚集体的组分与定位都不尽相同，它们都对抗泛素抗体有免疫活性，并且越来越多的研究证明，泛素依赖的蛋白酶体降解系统（Ub-proteasome system, UPS）的异常与蛋白质聚集体的形成紧密相关从而参与神经退行性病变[64,65].
（1）泛素化修饰与帕金森氏病。帕金森氏病（Parkinson's disease）以进行性的黑质多巴胺神经元丧失为特征，从而导致肌肉颤抖，震颤与运动迟缓。路易氏小体（Lewy bodies），主要由a-突触核蛋白（a-synuclein）组成的蛋白质聚集体，正是帕金森氏病的诊断特征，而大多数的路易氏小体中的a-突触核蛋白都处于单泛素化或双泛素化修饰的状态下[ 6 6 ].在培养的多巴胺能细胞中，泛素化似乎能增加蛋白质聚集程度与a-突触核蛋白的神经毒性[67].但是有趣的是，泛素化的效果具有位点特异性，不同赖氨酸位 点 的 泛 素 化 可 以 显 着 增 强 或 者 抑 制 原 纤 维 的形成[68].
（2）泛素化修饰与阿尔兹海默氏病。阿尔兹海默氏病（Alzheimer's disease）是老年人中最常见的神经退行性疾病，患有此病的病人会出现进展性的记忆丧失与认知障碍，并最终发展为痴呆。神经元胞外的b-淀粉样蛋白斑和胞内的神经原纤维缠结是阿尔兹海默氏病病人的病理特征之一，而二者正是由高度磷酸化与泛素化的tau蛋白组成的蛋白质聚集体。从阿尔兹海默氏病病人的脑组织标本与tau蛋白病变的小鼠模型的研究中发现， UPS效率的降低以及受到抑制的自噬-溶酶体通路与tau在突触末端的异常累积明显正相关[69,70].
3结论与展望
尽管许多泛素化修饰的原则得到了阐明，但泛素化修饰的生化机制与生理功能远未得到充分理解，例如，泛素化本身如何被调控以及泛素化与其他PTM如磷酸化、乙酰化之间的相互关系。本文简要介绍了泛素化的一些细胞生物学功能和泛素化异常参与的两种重要疾病-癌症与神经退行性疾病，尽管由于篇幅所限，许多泛素化参与的生物学过程与疾病未能详细阐述，但本文对了解泛素化的功能与意义的基本轮廓有所裨益。
未来的研究会进一步聚焦于泛素化修饰作为一个动态网络，如何参与生理学进程又怎样影响生物学功能。例如，不同的E2s与E3s之间的联系，不同的泛素化修饰种类（单泛素化、多泛素化以及多聚泛素化）以及不同的多聚泛素化链（连接通过Met1,Lys6, Lys11, Lys27, Lys29, Lys33, Lys48和Lys63）仍需进一步研究[71].与此同时，对于泛素化修饰的进一步理解也必将推动一系列相关疾病的研究与治疗，近期，线性泛素化通路（linear ubiquitination pathway）与炎症、肿瘤与自身免疫性疾病的相互关系取得了巨大突破，并有望为上述疾病的治疗提供新思路[72].因此，随着对泛素化修饰的深入研究与治疗技术的不断发展，对泛素化通路进行操作将成为一种富有前景的高度特异性的治疗方法。
参考文献：
1 Schwartz D C, Hochstrasser M. A superfamily of protein tags: ubiquitin, SUMO and related modifiers. Trends Biochem Sci, 2003, 28:321–328
2 Herrmann J, Lerman L O, Lerman A. Ubiquitin and ubiquitin-like proteins in protein regulation. Circ Res, 2007, 100: 1276–1291
3 Muratani M, Tansey W P. How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol, 2003, 4: 192–201
4 Shaid S, Brandts C H, Serve H, et al. Ubiquitination and selective autophagy. Cell Death Differ, 2013, 20: 21–30
5 Ulrich H D, Walden H. Ubiquitin signalling in DNA replication and repair. Nat Rev Mol Cell Biol, 2010, 11: 479–489
6 Vucic D, Dixit V M, Wertz I E. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol CellBiol, 2011, 12: 439–452
7 Haglund K, Dikic I. The role of ubiquitylation in receptor endocytosis and endosomal sorting. J Cell Sci, 2012, 125: 265–275
8 Goldstein G, Scheid M, Hammerling U, et al. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probablyrepresented universally in living cells. Proc Natl Acad Sci USA, 1975, 72: 11–15
9 Deshaies R J, Joazeiro C A. Ring domain E3 ubiquitin ligases. Annu Rev Biochem, 2009, 78: 399–434
10 Liu F, Walters K J. Multitasking with ubiquitin through multivalent interactions. Trends Biochem Sci, 2010, 35: 352–360
11 Xu P, Duong D M, Seyfried N T, et al. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomaldegradation. Cell, 2009, 137: 133–145
12 Rieser E, Cordier S M, Walczak H. Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem Sci, 2013, 38:94–102
13 Nijman S M, Luna-Vargas M P, Velds A, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell, 2005, 123: 773–786
14 Sowa M E, Bennett E J, Gygi S P, et al. Defining the human deubiquitinating enzyme interaction landscape. Cell, 2009, 138: 389–403
15 Petroski M D, Deshaies R J. Function and regulation of cullin-ring ubiquitin ligases. Nat Rev Mol Cell Biol, 2005, 6: 9–20
16 Schreiber A, Stengel F, Zhang Z, et al. Structural basis for the subunit assembly of the anaphase-promoting complex. Nature, 2011, 470:227–232
17 Sullivan M, Morgan D O. Finishing mitosis, one step at a time. Nat Rev Mol Cell Biol, 2007, 8: 894–903
18 Mocciaro A, Rape M. Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control. J Cell Sci, 2012, 125: 255–263
19 Chau V, Tobias J W, Bachmair A, et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science, 1989,243: 1576–1583
20 Glotzer M, Murray A W, Kirschner M W. Cyclin is degraded by the ubiquitin pathway. Nature, 1991, 349: 132–138
21 Thrower J S, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal. EMBO J, 2000, 19: 94–102
22 Jin L, Williamson A, Banerjee S, et al. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell, 2008,133: 653–665
23 Baboshina O V, Haas A L. Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by26S proteasome subunit 5. J Biol Chem, 1996, 271: 2823–2831
24 Matsumoto M L, Wickliffe K E, Dong K C, et al. K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specificantibody. Mol Cell, 2010, 39: 477–484
25 Williamson A, Wickliffe K E, Mellone B G, et al. Identification of a physiological E2 module for the human anaphase-promoting complex.Proc Natl Acad Sci USA, 2009, 106: 18213–18218
26 Reggiori F, Pelham H R. Sorting of proteins into multivesicular bodies: ubiquitin-dependent and -independent targeting. EMBO J, 2001, 20:5176–5186
27 Galan J M, Haguenauer-Tsapis R. Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein. EMBO J, 1997, 16:5847–5854
28 Huang F, Kirkpatrick D, Jiang X, et al. Differential regulation of EGF receptor internalization and degradation by multiubiquitination withinthe kinase domain. Mol Cell, 2006, 21: 737–748
29 Geetha T, Jiang J, Wooten M W. Lysine 63 polyubiquitination of the nerve growth factor receptor Trk A directs internalization andsignaling. Mol Cell, 2005, 20: 301–312
30 Duncan L M, Piper S, Dodd R B, et al. Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules.EMBO J, 2006, 25: 1635–1645
31 Joazeiro C A, Wing S S, Huang H, et al. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-proteinligase. Science, 1999, 286: 309–312
32 de Melker A A, van der Horst G, Calafat J, et al. c-Cbl ubiquitinates the EGF receptor at the plasma membrane and remains receptorassociated throughout the endocytic route. J Cell Sci, 2001, 114: 2167–2178
33 Sigismund S, Woelk T, Puri C, et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci USA, 2005, 102:2760–2765
34 Sigismund S, Argenzio E, Tosoni D, et al. Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable fordegradation. Dev Cell, 2008, 15: 209–219
35 Kazazic M, Bertelsen V, Pedersen K W, et al. Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits.Traffic, 2009, 10: 235–245
36 Sancar A, Lindsey-Boltz L A, Unsal-Kacmaz K, et al. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.Annu Rev Biochem, 2004, 73: 39–85
37 Hoeijmakers J H. Genome maintenance mechanisms are critical for preventing cancer as well as other aging-associated diseases. MechAgeing Dev, 2007, 128: 460–462
38 Huang T T, D'Andrea A D. Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol, 2006, 7: 323–334
39 D'Andrea A D. The fanconi road to cancer. Genes Dev, 2003, 17: 1933–1936
40 Wang X, Andreassen P R, D'Andrea A D. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. MolCell Biol, 2004, 24: 5850–5862
41 Garcia-Higuera I, Taniguchi T, Ganesan S, et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell,2001, 7: 249–262
42 Haupt Y, Maya R, Kazaz A, et al. Mdm2 promotes the rapid degradation of p53. Nature, 1997, 387: 296–299
43 Zilfou J T, Lowe S W. Tumor suppressive functions of p53. Cold Spring Harb Perspect Biol, 2009, 1: a001883
44 Jain A K, Barton M C. Making sense of ubiquitin ligases that regulate p53. Cancer Biol Ther, 2014, 10: 665–672
45 Broemer M, Tenev T, Rigbolt K T, et al. Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases. Mol Cell, 2010, 40:810–822
46 Hu S, Yang X. Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO. J Biol Chem, 2003,278: 10055–10060
47 Salvesen G S, Duckett C S. IAP proteins: blocking the road to death's door. Nat Rev Mol Cell Biol, 2002, 3: 401–410
48 Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAPinhibition. Cell, 2000, 102: 33–42
49 Schwartz A L, Ciechanover A. Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu RevPharmacol Toxicol, 2009, 49: 73–96
50 Hoeller D, Dikic I. Targeting the ubiquitin system in cancer therapy. Nature, 2009, 458: 438–444
51 Richardson P G, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med, 2003, 348:2609–2617
52 Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drugresistance in human multiple myeloma cells. Cancer Res, 2001, 61: 3071–3076
53 Vogelstein B, Kinzler K W. Cancer genes and the pathways they control. Nat Med, 2004, 10: 789–799
54 Wade M, Li Y C, Wahl G M. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer, 2013, 13: 83–96
55 Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-Tr CP: tipping the scales of cancer. Nat Rev Cancer,2008, 8: 438–449
56 Schmidt M H, Dikic I. The Cbl interactome and its functions. Nat Rev Mol Cell Biol, 2005, 6: 907–918
57 Gnarra J R, Tory K, Weng Y, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet, 1994, 7: 85–90
58 Kanno H, Kondo K, Ito S, et al. Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous systemhemangioblastomas. Cancer Res, 1994, 54: 4845–4847
59 Maxwell P H, Wiesener M S, Chang G W, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors foroxygen-dependent proteolysis. Nature, 1999, 399: 271–275
60 Xu L, Lubkov V, Taylor L J, et al. Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr Biol, 2010, 20:1372–1377
61 Kim S E, Yoon J Y, Jeong W J, et al. H-Ras is degraded by Wnt/beta-catenin signaling via beta-Tr CP-mediated polyubiquitylation. J CellSci, 2009, 122: 842–848
62 Baker R, Lewis S M, Sasaki A T, et al. Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function. NatStruct Mol Biol, 2013, 20: 46–52
63 Sasaki A T, Carracedo A, Locasale J W, et al. Ubiquitination of K-Ras enhances activation and facilitates binding to select downstreameffectors. Sci Signal, 2011, 4: ra13
64 Bennett E J, Bence N F, Jayakumar R, et al. Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic proteinaggregates precedes inclusion body formation. Mol Cell, 2005, 17: 351–365
65 Lam Y A, Pickart C M, Alban A, et al. Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. Proc Natl Acad Sci USA,2000, 97: 9902–9906
66 Tofaris G K, Razzaq A, Ghetti B, et al. Ubiquitination of alpha-synuclein in lewy bodies is a pathological event not associated withimpairment of proteasome function. J Biol Chem, 2003, 278: 44405–44411
67 Lee J T, Wheeler T C, Li L, et al. Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic celldeath. Hum Mol Genet, 2008, 17: 906–917
68 Meier F, Abeywardana T, Dhall A, et al. Semisynthetic, site-specific ubiquitin modification of alpha-synuclein reveals differential effectson aggregation. J Am Chem Soc, 2012, 134: 5468–5471
69 Tai H C, Serrano-Pozo A, Hashimoto T, et al. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease isassociated with dysfunction of the ubiquitin-proteasome system. Am J Pathol, 2012, 181: 1426–1435
70 Wang Y, Martinez-Vicente M, Kruger U, et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. HumMol Genet, 2009, 18: 4153–4170
71 Grabbe C, Husnjak K, Dikic I. The spatial and temporal organization of ubiquitin networks. Nat Rev Mol Cell Biol, 2011, 12: 295–307
72 Walczak H, Iwai K, Dikic I. Generation and physiological roles of linear ubiquitin chains. BMC Biol, 2012, 10: 23
相关标签：
