Department of Biochemistry and Molecular Biology, Medical School of Ningbo University, Key Laboratory of Pathophysiology of Zhejing Province, Ningbo 315211, Zhejiang, China
Abstract：Protein post-translational modification is a precondition guaranteeing normal exertion of protein functions. Ubiquitination is an important post-translational modification that maintains normal protein levels and activity. Numerous researches show that the E3 ubiquitin ligase speckle-type POZ protein (SPOP) displays mutations in many tumors and genetic diseases. Mainly concentrated in the MATH structural domain that recognizes substrates, these mutations influence the binding between SPOP and substrates, and further influence their protein levels, positioning and activities, thus disturbing the normal physiological functions. Wild-type SPOP binds the substrates, most of which enter the proteasome pathway for decomposition after being ubiquitinated by SPOP, but some substrates are also influenced functionally. Herein we review the ubiquitination types and functions of SPOP substrates, including the ubiquitin-proteasome system (UPS), structure, functions and molecular pathways of SPOP, and non-degradative ubiquitinated modification of SPOP. The emphasis will be laid on the molecular mechanisms of the signaling pathways mediated by the three non-degradative substrates of SPOP, that is, myeloid differentiation primary response gene 88 (MyD88)-mediated NF-κB pathway, X-chromosome silence signal pathway of histone macroH2A1 (macroH2A. 1 histone, macroH2A1), and inverted formin 2 (INF2)-mediated chondriokinesis pathway, in inhibiting tumorigenesis and development. We expect to provide a new perspective for precise targeted therapies of tumors.
林婷, 曹心怡, 金晓锋. E3泛素连接酶接头蛋白SPOP介导的底物非降解型泛素化修饰[J]. 中国生物化学与分子生物学报, 2021, 37(7): 874-882.
LIN Ting, CAO Xin-Yi, JIN Xiao-Feng. SPOP-mediated Non-degradative Ubiquitination. Chinese Journal of Biochemistry and Molecular Biol, 2021, 37(7): 874-882.
[1] Meyer-Schwesinger C. The ubiquitin-proteasome system in kidney physiology and disease [J]. Nat Rev Nephrol, 2019, 15(7): 393-411 [2] 倪晓光, 赵平. 泛素-蛋白酶体途径的组成和功能 [J]. 生理科学进展(Ni XG, Zhao P. The Composition and Biological Function of Ubiquitin-proteasome Pathway [J]. Prog Physiol Sci), 2006, 37 (3): 255-258 [3] Chen R-H. Cullin 3 and Its Role in Tumorigenesis [J]. Adv Exp Med Biol, 2020, 1217: 187-210 [4] Ji AX, Chu A, Nielsen TK, et al. Structural Insights into KCTD Protein Assembly and Cullin3 Recognition [J]. J Mol Biol, 2016, 428(1): 92-107 [5] Marzahn MR, Marada S, Lee J, et al. Higher-order oligomerization promotes localization of SPOP to liquid nuclear speckles [J]. EMBO J, 2016, 35(12): 1254-1275 [6] Cuneo MJ, Mittag T. The ubiquitin ligase adaptor SPOP in cancer [J]. FEBS J, 2019, 286(20): 3946-3958 [7] Kwon JE, La M, Oh KH, et al. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase [J]. J Biol Chem, 2006, 281(18): 12664- 12672 [8] Zhang Q, Shi Q, Chen Y, et al. Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase [J]. Proc Natl Acad Sci U S A, 2009, 106(50): 21191-21196 [9] Geng C, He B, Xu L, et al. Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover [J]. Proc Natl Acad Sci U S A, 2013, 110(17): 6997-7002 [10] An J, Wang C, Deng Y, et al. Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants [J]. Cell Rep, 2014, 6(4): 657-669 [11] An J, Ren S, Murphy SJ, et al. Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation [J]. Mol Cell, 2015, 59(6): 904-916 [12] Dai X, Gan W, Li X, et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4 [J]. Nat Med, 2017, 23(9): 1063-1071 [13] Fennell KA, Dawson MA. SPOP tips the balance of BETs in cancer [J]. Nat Med, 2017, 23(9): 1014-1015 [14] Janouskova H, El Tekle G, Bellini E, et al. Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors [J]. Nat Med, 2017, 23(9): 1046-1054 [15] Zhang P, Wang D, Zhao Y, et al. Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation [J]. Nat Med, 2017, 23(9): 1055- 1062 [16] Luo L, Tang H, Ling L, et al. LINC01638 lncRNA activates MTDH-Twist1 signaling by preventing SPOP- mediated c-Myc degradation in triple-negative breast cancer [J]. Oncogene, 2018, 37(47): 6166- 6179 [17] Li C, Ao J, Fu J, et al. Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1 [J]. Oncogene, 2011, 30(42): 4350-4364 [18] Gao K, Jin X, Tang Y, et al. Tumor suppressor SPOP mediates the proteasomal degradation of progesterone receptors (PRs) in breast cancer cells [J]. Am J Cancer Res, 2015, 5(10): 3210-3220 [19] Xu J, Wang F, Jiang H, et al. Properties and Clinical Relevance of Speckle-Type POZ Protein in Human Colorectal Cancer [J]. J Gastrointest Surg, 2015, 19(8): 1484-1496 [20] Tan Y, Ci Y, Dai X, et al. Cullin 3SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6 [J]. Oncotarget, 2017, 8(29): 47890-47901 [21] Zhi X, Tao J, Zhang L, et al. Silencing speckle-type POZ protein by promoter hypermethylation decreases cell apoptosis through upregulating Hedgehog signaling pathway in colorectal cancer [J]. Cell Death Dis, 2016, 7(12): e2569 [22] DeLair DF, Burke KA, Selenica P, et al. The genetic landscape of endometrial clear cell carcinomas [J]. J Pathol, 2017, 243(2): 230-241 [23] Le Gallo M, Rudd ML, Urick ME, et al. Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing [J]. Cancer, 2017, 123(17): 3261-3268 [24] Le Gallo M, O'Hara AJ, Rudd ML, et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes [J]. Nat Genet, 2012, 44(12): 1310-1315 [25] Le Gallo M, Bell DW. The emerging genomic landscape of endometrial cancer [J]. Clin Chem, 2014, 60 (1): 98-110 [26] Zhang P, Gao K, Jin X, et al. Endometrial cancer-associated mutants of SPOP are defective in regulating estrogen receptor-α protein turnover [J]. Cell Death Dis, 2015, 6(3): e1687 [27] Zeng C, Wang Y, Lu Q, et al. SPOP suppresses tumorigenesis by regulating Hedgehog/Gli2 signaling pathway in gastric cancer [J]. J Exp Clin Cancer Res, 2014, 33(1): 75 [28] Jia D, Dong R, Jing Y, et al. Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex [J]. Hepatology, 2014, 60(5): 1686-1696 [29] Huang Y, Tan N, Jia D, et al. Speckle-type POZ protein is negatively associated with malignancies and inhibits cell proliferation and migration in liver cancer [J]. Tumour Biol, 2015, 36(12): 9753-9761 [30] Ji P, Liang S, Li P, et al. Speckle-type POZ protein suppresses hepatocellular carcinoma cell migration and invasion via ubiquitin-dependent proteolysis of SUMO1/sentrin specific peptidase 7 [J]. Biochem Biophys Res Commun, 2018, 502(1): 30-42 [31] Harb OA, Elfeky MA, El Shafaay BS, et al. SPOP, ZEB-1 and E-cadherin expression in clear cell renal cell carcinoma (cc-RCC): Clinicopathological and prognostic significance [J]. Pathophysiology, 2018, 25(4): 335-345 [32] Chauhan A, Bhattacharyya S, Ojha R, et al. Speckle-type POZ protein as a diagnostic biomarker in renal cell carcinoma [J]. J Cancer Res Ther, 2018, 14(5): 977-982 [33] Zhao W, Zhou J, Deng Z, et al. SPOP promotes tumor progression via activation of β-catenin/TCF4 complex in clear cell renal cell carcinoma [J]. Int J Oncol, 2016, 49(3): 1001-1008 [34] Li G, Ci W, Karmakar S, et al. SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer [J]. Cancer Cell, 2014, 25(4): 455-468 [35] Luo J, Bao Y-C, Ji X-X, et al. SPOP promotes SIRT2 degradation and suppresses non-small cell lung cancer cell growth [J]. Biochem Biophys Res Commun, 2017, 483(2): 880-884 [36] Luo J, Chen B, Gao C-X, et al. SPOP promotes FADD degradation and inhibits NF-κB activity in non-small cell lung cancer [J]. Biochem Biophys Res Commun, 2018, 504(1): 289-294 [37] Kan Z, Jaiswal BS, Stinson J, et al. Diverse somatic mutation patterns and pathway alterations in human cancers [J]. Nature, 2010, 466(7308): 869-873 [38] Berger MF, Lawrence MS, Demichelis F, et al. The genomic complexity of primary human prostate cancer [J]. Nature, 2011, 470(7333): 214-220 [39] Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer [J]. Nat Genet, 2012, 44(6): 685-689 [40] Romanel A, Garritano S, Stringa B, et al. Inherited determinants of early recurrent somatic mutations in prostate cancer [J]. Nat Commun, 2017, 8(1): 48 [41] Jung S-H, Shin S, Kim MS, et al. Genetic Progression of High Grade Prostatic Intraepithelial Neoplasia to Prostate Cancer [J]. Eur Urol, 2016, 69(5): 823-830 [42] Hjorth-Jensen K, Maya-Mendoza A, Dalgaard N, et al. SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability [J]. Nucleic Acids Res, 2018, 46(18): 9484-9495 [43] Boysen G, Barbieri CE, Prandi D, et al. SPOP mutation leads to genomic instability in prostate cancer [J]. Elife, 2015, 4: e09207 [44] Claiborn KC, Sachdeva MM, Cannon CE, et al. Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice [J]. J Clin Invest, 2010, 120(10): 3713-3721 [45] Blattner M, Liu D, Robinson BD, et al. SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling [J]. Cancer Cell, 2017, 31(3): 436-451 [46] García-Flores M, Casanova-Salas I, Rubio-Briones J, et al. Clinico-pathological significance of the molecular alterations of the SPOP gene in prostate cancer [J]. Eur J Cancer, 2014, 50(17): 2994-3002 [47] Geng C, Rajapakshe K, Shah SS, et al. Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer [J]. Cancer Res, 2014, 74(19): 5631-5643 [48] Groner AC, Cato L, de Tribolet-Hardy J, et al. TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer [J]. Cancer Cell, 2016, 29(6): 846-858 [49] Geng C, Kaochar S, Li M, et al. SPOP regulates prostate epithelial cell proliferation and promotes ubiquitination and turnover of c-MYC oncoprotein [J]. Oncogene, 2017, 36(33): 4767-4777 [50] Theurillat J-PP, Udeshi ND, Errington WJ, et al. Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer [J]. Science, 2014, 346(6205): 85-89 [51] Zhu H, Ren S, Bitler BG, et al. SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase [J]. Cell Rep, 2015, 13(6): 1183-1193 [52] Zhang L, Peng S, Dai X, et al. Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells [J]. Cancer Lett, 2017, 390: 11-20 [53] Ma J, Chang K, Peng J, et al. SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression [J]. J Exp Clin Cancer Res, 2018, 37(1): 145 [54] Wu F, Dai X, Gan W, et al. Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation [J]. Cancer Lett, 2017, 385: 207-214 [55] Gan W, Dai X, Lunardi A, et al. SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression [J]. Mol Cell, 2015, 59(6): 917-930 [56] Zhang J, Bu X, Wang H, et al. Author Correction: Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance [J]. Nature, 2019, 571(7766): E10 [57] Ju L-G, Zhu Y, Long Q-Y, et al. SPOP suppresses prostate cancer through regulation of CYCLIN E1 stability [J]. Cell Death Differ, 2019, 26(6): 1156-1168 [58] Zhang P, Gao K, Tang Y, et al. Destruction of DDIT3/CHOP protein by wild-type SPOP but not prostate cancer-associated mutants [J]. Hum Mutat, 2014, 35(9): 1142-1151 [59] Jin X, Shi Q, Li Q, et al. CRL3-SPOP ubiquitin ligase complex suppresses the growth of diffuse large B- cell lymphoma by negatively regulating the MyD88/NF-κB signaling [J]. Leukemia, 2020, 34(5): 1305- 1314 [60] Hu Y-H, Wang Y, Wang F, et al. SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association [J]. Cell Mol Immunol, 2020, doi: 10.1038/s41423-020-0411-1 [61] Hernández-Muñoz I, Lund AH, van der Stoop P, et al. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase [J]. Proc Natl Acad Sci U S A, 2005, 102(21): 7635-7640 [62] Jin X, Wang J, Gao K, et al. Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer [J]. PLoS Genet, 2017, 13(4): e1006748 [63] Deguine J, Barton GM. MyD88: a central player in innate immune signaling [J]. F1000Prime Rep, 2014, 6: 97 [64] Wang L, Yu K, Zhang X, et al. Dual functional roles of the MyD88 signaling in colorectal cancer development [J]. Biomed Pharmacother, 2018, 107: 177-184 [65] Echizen K, Hirose O, Maeda Y, et al. Inflammation in gastric cancer: Interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD88 pathways [J]. Cancer Sci, 2016, 107(4): 391-397 [66] Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MyD88 mutations in human lymphoma [J]. Nature, 2011, 470(7332): 115-119 [67] Ansell SM, Hodge LS, Secreto FJ, et al. Activation of TAK1 by MyD88 L265P drives malignant B-cell Growth in non-Hodgkin lymphoma [J]. Blood Cancer J, 2014, 4(2): e183 [68] Phelan JD, Young RM, Webster DE, et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma [J]. Nature, 2018, 560(7718): 387-391 [69] Kiel MJ, Velusamy T, Betz BL, et al. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma [J]. J Exp Med, 2012, 209(9): 1553-1565 [70] Boudesco C, Verhoeyen E, Martin L, et al. HSP110 sustains chronic NF-κB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization [J]. Blood, 2018, 132(5): 510-520 [71] Ni H, Shirazi F, Baladandayuthapani V, et al. Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191 [J]. Clin Cancer Res, 2018, 24(24): 6408-6420 [72] Rousseau S, Martel G. Gain-of-Function Mutations in the Toll-Like Receptor Pathway: TPL2-Mediated ERK1/ERK2 MAPK Activation, a Path to Tumorigenesis in Lymphoid Neoplasms? [J]. Front Cell Dev Biol, 2016, 4: 50 [73] Guillamot M, Ouazia D, Dolgalev I, et al. The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MyD88 degradation [J]. Nat Immunol, 2019, 20(9): 1196-1207 [74] Li Q, Wang F, Wang Q, et al. SPOP promotes ubiquitination and degradation of MyD88 to suppress the innate immune response [J]. PLoS Pathog, 2020, 16(5): e1008188 [75] Novikov L, Park JW, Chen H, et al. QKI-mediated alternative splicing of the histone variant MacroH2A1 regulates cancer cell proliferation [J]. Mol Cell Biol, 2011, 31(20): 4244-4255 [76] Wang D, Tang L, Wu Y, et al. Abnormal X chromosome inactivation and tumor development [J]. Cell Mol Life Sci, 2020, 77(15): 2949-2958 [77] Cantone I, Fisher AG. Human X chromosome inactivation and reactivation: implications for cell reprogramming and disease [J]. Philos Trans R Soc Lond B Biol Sci, 2017, 372(1733): 20160358 [78] Labat-de-Hoz L, Alonso MA. The formin INF2 in disease: progress from 10 years of research [J]. Cell Mol Life Sci, 2020, 77(22): 4581-4600 [79] Chhabra ES, Ramabhadran V, Gerber SA, et al. INF2 is an endoplasmic reticulum-associated formin protein [J]. J Cell Sci, 2009, 122(Pt 9): 1430-1440 [80] Ramabhadran V, Korobova F, Rahme GJ, et al. Splice variant-specific cellular function of the formin INF2 in maintenance of Golgi architecture [J]. Mol Biol Cell, 2011, 22(24): 4822-4833 [81] Boyer O, Nevo F, Plaisier E, et al. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy [J]. N Engl J Med, 2011, 365(25): 2377-2388 [82] Korobova F, Ramabhadran V, Higgs HN. An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2 [J]. Science, 2013, 339(6118): 464-467 [83] 许美芬, 何轶群, 管敏鑫. 线粒体融合、分裂与神经变性疾病[J]. 中国生物化学与分子生物学报(Xu MF, He YQ, Guan MX. Deregulation of Mitochondrial Fusion and Fission in Neurodegenerative Diseases [J]. Chin J Biochem Mol Biol), 2013, 29(12): 1113-1119 [84] Maycotte P, Marín-Hernández A, Goyri-Aguirre M, et al. Mitochondrial dynamics and cancer [J]. Tumour Biol, 2017, 39(5): 1010428317698391 [85] Srinivasan S, Guha M, Kashina A, et al. Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection [J]. Biochim Biophys Acta Bioenerg, 2017, 1858(8): 602-614 [86] Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer [J]. Curr Opin Cell Biol, 2016, 39: 43-52 [87] da Silva AF, Mariotti FR, Máximo V, et al. Mitochondria dynamism: of shape, transport and cell migration [J]. Cell Mol Life Sci, 2014, 71(12): 2313-2324 [88] Guo ZQ, Zheng T, Chen B, et al. Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer [J]. Cancer Cell, 2016, 30(3): 474-484 [89] Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic [J]. Nature, 2010, 468(7327): 1119-1123 [90] Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains [J]. Nature, 2010, 468 (7327): 1067-1073
