Richard JH Wojcikiewicz, PhD
CURRENT APPOINTMENTS
LANGUAGES
WEB RESOURCES
RESEARCH PROGRAMS AND AFFILIATIONS
RESEARCH INTERESTS
通过InsP3受体的细胞内信号传导及其通过泛素/蛋白酶体途径和Bcl-2家族蛋白的调控.
EDUCATION INTERESTS
Current Graduate Students are: Laura Szczesniak (MD/PhD), Jenson Gao (PhD), Fanghui Hua (PhD) and Caden Bonzerato (PhD)
EDUCATION
RESEARCH ABSTRACT
IP3 receptor regulation, the ubiquitin / proteasome pathway, the Bcl-2 protein family and intracellular signaling
IP3是一种细胞内信使分子，当激素作用于质膜时形成, neurotransmitters or drugs stimulate cells. The effects of IP3 are mediated by proteins called IP3 receptors, 控制钙离子从内质网释放到细胞质溶胶的通道:这种“钙动员”是许多细胞功能的核心部分. 我的实验室研究IP3受体生物化学和分子生物学的各个方面已经有一段时间了. 我们目前的主要重点是分析IP3受体的下调——这是一种显著的现象，当IP3受体受到刺激时，它们会迅速从细胞中消失(见图)。. 这是一种典型的适应性反应，使细胞能够适应外部环境，发生在慢性药物暴露期间，也可能发生在生理和病理情况下. 我们目前正在研究IP3受体下调的机制，发现其发生是由于IP3受体被泛素标记，然后被蛋白体降解. 这是令人兴奋的，因为泛素/蛋白体途径目前是细胞生物学的“热点领域”之一，越来越明显的是，这一途径是许多重要的细胞蛋白和内质网中错误折叠蛋白被降解的机制，并且与疾病(如疾病)具有重要的相关性.g. cancer, neurodegeneration, diabetes). Our immediate goals, then, 在分子水平上定义通过泛素/蛋白酶体途径导致IP3受体降解的途径并开始构建何时的图景, why and how cellular proteins are tagged with ubiquitin. As depicted in the diagram, 近年来，我们发现IP3受体泛素化是由erlin1和erlin2蛋白组成的新复合物介导的, and the ubiquitin ligase RNF170, 两种泛素链类型(K48-linked和K63-linked)与活化的IP3受体偶联. Using advanced techniques (e.g. 我们现在正在结构水平上定义IP3受体和erlin1/2复合物是如何相互作用的. 第二个重点是表征Bcl-2家族蛋白(控制细胞凋亡)与IP3受体的相互作用. We recently discovered that Bok (“Bcl-2-Related Ovarian K“iller”)组成性地结合IP3受体，并定义了这种相互作用的重要性. Because of the importance of IP3 receptors, the ubiquitin / proteasome pathway, and the Bcl-2 protein family to cell biology, this work is significant to both our understanding of normal physiology, and also to diseases, such as cancer and neurodegeneration.
Recent Publications
58. Pearce, M.M., Wang, Y., Kelley, G.G. and Wojcikiewicz, R.J.H. (2007)在哺乳动物细胞中，SPFH2介导IP3受体和其他底物的ERAD. J. Biol. Chem. 282, 20104-20115.
59. Hanson, C.J., Bootman, M.D., Distelhorst, C.W., Wojcikiewicz, R.J.H. and Roderick, H.L. (2008) Bcl-2 suppresses Ca2+ release through inositol 1,4,5-三磷酸受体和抑制Ca2+摄取线粒体而不影响内质网钙储存含量. Cell Calcium 44, 324-338.
60. Ito, J., Yoon, S-Y., Lee, B., Vanderhayden, V., Vermassen, E., Wojcikiewicz, R.J.H., Alfandari, D., De Smedt, H., Parys, J.B. and Fissore, R.A. (2008) Inositol 1,4,5-trisphosphate receptor 1, a widespread Ca2+ channel, is a novel substrate of polo-like kinase 1 in eggs. Dev. Biol. 320, 402-413.
61. Kuo, I.Y., Chan-Ling, T., Wojcikiewicz, R.J.H. and Hill, C.E. (2008)啮齿动物脑干和视网膜有限的血管内耦合支持神经胶质在局部血流中的作用. J. Comp. Neurol. 511, 773-787.
62. Sliter, D., Kirkpatrick, D.S., Alzayady, K., Kubota, K., Gygi, S.P. and Wojcikiewicz, R.J.H. (2008) I型肌醇1,4,5-三磷酸受体泛素化的质谱分析. J. Biol. Chem. 283, 35319-35328.
63. Ellis, A., Goto, K., Brackenbury, T.D., Meaney, K.R., Falck, J.R., Wojcikiewicz, R.J.H. and Hill, C.E. (2009)血管紧张素ii: EETs和间隙连接在大鼠肠系膜动脉EDHF活性介导中的作用依赖性. J. Pharmacol. Exp. Ther. 330, 413-422.
64. Pearce, M.M.P., Wormer, D.B., Wilkens, S. and Wojcikiewicz, R.J.H. (2009)由SPFH1和SPFH2组成的内质网膜复合物可介导内质网相关的IP3受体降解. J. Biol. Chem. 284, 10433-10445.
65. Brodsky, J.L. and Wojcikiewicz R.J.H. (2009) Substrate specific mediators of ER associated degradation (ERAD). Curr. Opin. Cell Biol. 21, 516-21.
66. Wojcikiewicz, R.J.H., Pearce, M.M.P., Sliter, D. and Wang. Y. (2009) When worlds collide: IP3 receptors and the ERAD pathway. Cell Calcium 46, 147-153.
67. Wang, Y., Pearce, M.M.P., Sliter, D., Olzmann, J.A., Christianson, J.C., Kopito, R.R., Boeckmann, S., Gagen, C., Leichner, G., Roitelman, J. and Wojcikiewicz, R.J.H. (2009) SPFH1和SPFH2介导肌醇1的泛素化和降解,4,5-trisphosphate receptors in muscarinic receptor-expressing HeLa cells. BBA 1793, 1710-1718
68. Sliter D.A., Aguiar, M., Gygi, S.P. and Wojcikiewicz, R.J.H. (2011) Activated inositol 1,4,5-三磷酸受体被均相的LYS48-和lys63 -连接的泛素链修饰, but only LYS48-linked chains are required for degradation. J. Biol. Chem. 286, 1074-1082.
69. Lu, J.P., Wang, Y., Sliter, D.A., Pearce, M.M.P. and Wojcikiewicz, R.J.H. (2011) RNF170, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation. J. Biol. Chem. 286, 24426-24433.
70. Pednekar, D., Wang, Y., Fedotova, T.V. and Wojcikiewicz, R.J.H. (2011)疏水氨基酸聚集在两亲螺旋中介导erlin 1 / 2复合物的组装. Biochem. Biophys. Res. Commun. 415, 135-140.
71. Wojcikiewicz, R.J.H. (2012) Inositol 1,4,5-trisphosphate receptor degradation pathways. WIREs Membr. Transp. Signal. 1, 126-135.
72. Tsai, Y.C., Leichner, G.S., Pearce, M.M., Wilson, G.L., Wojcikiewicz, R.J., Roitelman, J. and Weissman, A.M. (2012)泛素-蛋白酶体系统酶对HMG-CoA还原酶和insg -1的差异调控. Mol. Biol. Cell. 23, 4484-4494.
73. Hirose, M., Kamoshita, M., Fujiwara, K., Kato, T., Nakamura, A., Wojcikiewicz, R.J.H., Parys, J.B., Ito, J. and Kashiwazaki, N. (2013) Vitrification procedure decreases inositol 1,4,5-trisphosphate receptor expression, resulting in low fertility of pig oocytes. Animal Sci. J. (in press).
74. Schulman, J.J., Wright, F.A., Kaufmann, T and Wojcikiewicz, R.J.H. (2013) Bcl-2蛋白家族成员Bok与肌醇1偶联结构域结合,4,5-trisphosphate receptors and protects them from proteolytic cleavage. J. Biol. Chem. 288, 25340-25349.
75. Sathanawongs, A., Fujiwara, K., Kato, T., Hirose, M., Kamoshita, M., Wojcikiewicz, R.J.H., Parys, J.B., Ito, J. and Kashiwazaki, N. (2015) m期阶段依赖性激酶抑制剂对肌醇的影响,4,5-triphosphate receptor 1 (IP3R1) expression and localization in pig oocytes. Animal Sci. J. 86, 138-147.
76. Wright, F.A., Lu, J.P., Sliter, D.A., Dupré, N., Rouleau, G.A. and Wojcikiewicz, R.J.H. (2015)泛素连接酶RNF170的点突变导致常染色体显性感觉共济失调，使蛋白质不稳定并损害肌醇1,4,5-trisphosphate receptor-mediated Ca2+ signaling. J. Biol. Chem. 290, 13948-13957.
77. Schulman, J.J., Wright, F.A., Han, X., Zluhan, E.J., Szczesniak, L.M. and Wojcikiewicz, R.J.H. (2016) Bok结合蛋白的稳定性和表达水平受与肌醇1结合的影响,4,5-trisphosphate receptors. J. Biol. Chem. 291, 11820-11828.
78. Wright, F.A. and Wojcikiewicz, R.J.H. (2016) Inositol 1,4,5-trisphosphate receptor ubiquitination. Prog. Mol. Biol. Trans. Sci. 141, 141-159.
79. Wang, L., Shi, C., Wright, F.A., Guo, D., Wang, X., Wang, D., Wojcikiewicz, R.J.H. and Luo, J. (2017)硼替佐米与阿霉素在卵巢癌治疗中的协同作用. Cancer Res. 77, 3293 - 3305.
80. Wojcikiewicz, R.J.H. (2018)肌醇1,4,5 -三磷酸受体四聚体的合成与分解. Messenger 6, 45-49.
81. Wright, F.A., Bonzerato, C.G., Sliter, D.A. and Wojcikiewicz, R.J.H. (2018) erlin2 T65I突变抑制erlin1/2复合物介导的肌醇1,4,5-三磷酸受体泛素化与磷脂酰肌醇3-磷酸结合. J. Biol. Chem. 293, 15706-15714.
82. Schulman, J.J., Szczesniak, L.M., Bunker, E.N., Nelson, H.A., Roe, M.W., Wagner II, L.A., Yule, D.I. and Wojcikiewicz, R.J.H. (2019) Bok regulates mitochondrial fusion and morphology. Cell Death and Diff. doi: 10.1038/s41418-019-0327-4.83.
83. Gao, X. and Wojcikiewicz, R.J.H. (2020) IP3受体转换与遗传性痉挛性截瘫之间的新联系. Cell Calcium 86:102142. doi: 10.1016/j.ceca.2019.102142.
84. Dong, Y., Lee, Y., Cui, K., He, M., Wang, B., Bhattacharjee, S., Zhu, B., Yago, T., Zhang, K., Deng, L., Ouyang, K., Wen, A., Cowan, D.B., Song, K., Yu, L., Brophy, M.L., Liu, X., Wylie-Sears, J., Wu, H., Wong, S., Cui, G., Kawashima, Y., Matsumoto, H., Kodera, Y., Wojcikiewicz, R.J.H., Srivastava, S., Bischoff, J., Wang, D.Z., Ley, K., Chen, H. (2020) Epsin-mediated degradation of IP3R1 fuels atherosclerosis. Nat. Commun. 11(1):3984. doi: 10.1038/s41467-020-17848-4.
85. Szczesniak, L.M., Bonzerato, C.G., Schulman, J.J., Bah, A. and Wojcikiewicz, R.J.H. (2021) Bok与1型肌醇1偶联域的一个很大程度上无序的环结合,4,5-trisphosphate receptor. Biochem. Biophys. Res Commun. 553, 180-186.
86. Szczesniak, L.M., Bonzerato, C.G. and Wojcikiewicz, R.J.H. (2021) Identification of the Bok interactome using proximity labeling. Front. Cell Dev. Biol. 9:689951. doi: 10.3389/fcell.2021.689951.
87. Gao, X., Bonzerato, C.G. and Wojcikiewicz, R.J.H. (2022) Binding of the erlin1/2 complex to the third intralumenal loop of IP3R1 triggers its ubiquitin-proteasomal degradation. J. Biol. Chem. 298, 102026.
88. Bonzerato, C.G., Keller, K.R., Schulman, J.J., Gao, X., Szczesniak, L.M. and Wojcikiewicz, R.J.H. (2022)内源性Bok在内质网稳定，不介导蛋白酶体抑制剂诱导的细胞凋亡. Frontiers in Cell and Dev Biol. 10, 1094302. doi: 10.3389/fcell.2022.1094302.