WEB资源
研究项目和附属机构
研究兴趣
Intracellular signaling via InsP3 receptors and their regulation by the ubiquitin/proteasome pathway and Bcl-2 family proteins.
教育利益
Laura Szczesniak(医学博士/博士), 高简森(博士), 华方辉(PhD)， Caden Bonzerato (PhD)
教育
研究抽象
IP3受体调控, 泛素/蛋白酶体途径, Bcl-2蛋白家族和细胞内信号传导
IP3 is an intracellular messenger molecule formed at the plasma membrane when hormones, 神经递质或药物刺激细胞. IP3的作用是由称为IP3受体的蛋白质介导的, channels that govern the release of calcium ions from the endoplasmic reticulum into the cell cytosol: this "calcium mobilization" is a central part of many cellular functions. My laboratory has been studying various aspects of IP3 receptor biochemistry and molecular biology for some time. Our primary focus at the moment is analyzing IP3 receptor down-regulation - a remarkable phenomenon by which IP3 receptors are rapidly depleted from cells when they are stimulated (see diagram). This is a classic adaptive response that enables cells to adjust to their external environment and occurs during chronic exposure to drugs and perhaps in physiological and pathological situations. We are currently investigating the mechanism of IP3 receptor down-regulation and have discovered that it occurs because IP3 receptors are tagged with ubiquitin and 然后 degraded by the proteosome. This is exciting because the ubiquitin / proteosome pathway is currently one of the "hot areas" of cell biology - is it becoming increasingly apparent that this pathway is the mechanism by which many important cellular proteins and misfolded proteins in the endoplasmic reticulum are degraded and is of major relevance to diseases (e.g. 癌症、神经变性、糖尿病). 我们的近期目标, 然后, are to define at the molecular level the pathway that leads to IP3 receptor degradation via 泛素/蛋白酶体途径 and to begin to build a picture of when, 为什么以及如何用泛素标记细胞蛋白. 如图所示, in recent years we have discovered that IP3 receptor ubiquitination is mediated by a novel complex composed of the proteins erlin1 and erlin2, 以及泛素连接酶RNF170, and that two ubiquitin chain types (K48-linked and K63-linked) are coupled to activated IP3 receptors. 使用先进的技术(如.g. cryo-EM) we are now defining at the structural level how IP3 receptors and the erlin1/2 complex interact. A second focus is characterizing the interaction of Bcl-2 family proteins (that control apoptosis) with IP3 receptors. 我们最近发现布克(”Bcl-2-R得意洋洋的 O瓦里安 Killer”) binds constitutively to IP3 receptors and are defining the significance of this interaction. 因为IP3受体的重要性, 泛素/蛋白酶体途径, 以及Bcl-2蛋白家族对细胞生物学的影响, 这项工作对我们对正常生理学的理解都很重要, 还有疾病, 比如癌症和神经退化.
最近的出版物
58. 皮尔斯,M.M.王，Y.凯利，G.G. 沃基凯维奇，R.J.H. (2007) SPFH2 mediates the ERAD of IP3 receptors and other substrates in mammalian cells. J. 医学杂志. 化学. 282, 20104-20115.
59. 汉森,C.J.布特曼，M.D.C.W.沃基凯维奇，R.J.H. 罗德里克，H.L. (2008) Bcl-2通过肌醇1抑制Ca2+释放,4,5-trisphosphate受体 and inhibits Ca2+ uptake by mitochondria without affecting ER calcium store content. 细胞钙44,324-338.
60. 伊藤J.Yoon, S-Y.李，B.范德海登，V.Vermassen, E.沃基凯维奇，R.J.H.阿尔凡达里，D.德·斯梅特，H.帕里斯，J.B. 费索，R.A. (2008)肌醇,4,5-三磷酸受体, 广泛的Ca2+通道, 卵中有一种新的球样激酶1底物吗. Dev. 医学杂志. 320, 402-413.
61. 郭,我.Y.陈玲，T.沃基凯维奇，R.J.H. 希尔，C。.E. (2008) Limited intravascular coupling in the rodent brainstem and retina supports a role for glia in regional blood flow. J. 电脑及相关知识. 神经. 511, 773-787.
62. 纵割机,D.D .柯克帕特里克.S.Alzayady, K.久保田，K.吉吉，S.P. 沃基凯维奇，R.J.H. (2008) Mass spectral analysis of type I inositol 1,4,5-trisphosphate受体 ubiquitination. J. 医学杂志. 化学. 283, 35319-35328.
63. 艾利斯,.， Goto, K.布拉肯伯里，T.D.米尼，K.R.福尔克，J.R.沃基凯维奇，R.J.H. 希尔，C。.E. (2009) Angiotensin II-dependency of the role of EETs and gap junctions in mediating EDHF activity in rat mesenteric arteries. J. 杂志. 经验值. 其他. 330, 413-422.
64. 皮尔斯,M.M.P.沃莫，D.B.威尔肯斯，S. 沃基凯维奇，R.J.H. (2009) An ER membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of IP3 receptors. J. 医学杂志. 化学. 284, 10433-10445.
65. 布罗斯基,J.L. 和沃基凯维奇R.J.H. (2009)内质网相关降解(ERAD)的底物特异性介质. 咕咕叫. 当今. 细胞生物. 21, 516-21.
66. Wojcikiewicz R.J.H.皮尔斯，M.M.P.斯里尔，D. 和王. Y. (2009)当世界碰撞:IP3受体和ERAD通路. 细胞钙46,147-153.
67. 王,Y.皮尔斯，M.M.P.斯里尔，D.奥尔兹曼，J.A.J .克里斯蒂安森.C.， Kopito, R.R.伯克曼，S.加根，C.莱希纳，G.罗特尔曼，J. 沃基凯维奇，R.J.H. (2009) SPFH1 and SPFH2 mediate the ubiquitination and degradation of inositol 1,4,表达毒蕈碱受体的HeLa细胞中的5-三磷酸受体. 1793, 1710-1718
68. 纵割机维.A.阿吉亚尔，M.吉吉，S.P. 沃基凯维奇，R.J.H. (2011)活化肌醇1,4,5-trisphosphate受体 are modified by homogeneous LYS48- and LYS63-linked ubiquitin chains, 但降解只需要lys48链. J. 医学杂志. 化学. 286, 1074-1082.
69. 陆,J.P.王，Y.斯里尔，D.A.皮尔斯，M.M.P. 沃基凯维奇，R.J.H. (2011) RNF170, 一种内质网膜泛素连接酶, 介导肌醇1,4,5-三磷酸受体泛素化和降解. J. 医学杂志. 化学. 286, 24426-24433.
70. Pednekar D.王，Y.费多托娃，T.V. 沃基凯维奇，R.J.H. (2011) Clustered hydrophobic amino acids in amphipathic helices mediate erlin 1 / 2 complex assembly. 物化学. Biophys. Res. Commun. 415, 135-140.
71. Wojcikiewicz R.J.H. (2012)肌醇1,4,5-三磷酸受体降解途径. 电线会员. 透明. 信号. 1, 126-135.
72. 蔡,Y.C.莱希纳，G.S.皮尔斯，M.M.威尔逊，G.L.沃基凯维奇，R.J.罗特尔曼，J. 魏斯曼，A.M. (2012) Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. 摩尔. 医学杂志. 细胞. 23, 4484-4494.
73. Hirose, M.Kamoshita, M.藤原，K.加藤，T.Nakamura, A.沃基凯维奇，R.J.H.帕里斯，J.B.伊藤，J. 柏崎，n.n. (2013)玻璃化过程降低肌醇1,4,5-三磷酸受体表达, 导致猪卵母细胞生育能力低下. 动物科学. J. (新闻).
74. 舒尔曼J.J.赖特，F.A.，考夫曼，T和沃基凯维奇，R.J.H. (2013) The Bcl-2 protein family member Bok binds to the coupling domain of inositol 1,4,5-三磷酸受体并保护它们免受蛋白水解裂解. J. 医学杂志. 化学. 288, 25340-25349.
75. Sathanawongs,.藤原，K.加藤，T.广濑，M.Kamoshita, M.沃基凯维奇，R.J.H.帕里斯，J.B.伊藤，J. 柏崎，n.n. (2015) The effect of M-phase stage-dependent kinase inhibitors on inositol 1,4,5-三磷酸受体1 (IP3R1)在猪卵母细胞中的表达和定位. 动物科学. J. 86, 138-147.
76. 赖特,F.A.卢，J.P.斯里尔，D.A.纽约州杜普莱尔(duprire.鲁洛，G.A. 沃基凯维奇，R.J.H. (2015) A point mutation in the ubiquitin ligase RNF170 that causes autosomal dominant sensory ataxia destabilizes the protein and impairs inositol 1,4,5-三磷酸受体介导的Ca2+信号. J. 医学杂志. 化学. 290, 13948-13957.
77. 舒尔曼J.J.赖特，F.A.汉，X.Zluhan, E.J.斯切斯尼亚克，L.M. 沃基凯维奇，R.J.H. (2016) The stability and expression level of Bok binds are governed by binding to inositol 1,4,5-trisphosphate受体. J. 医学杂志. 化学. 291, 11820-11828.
78. 赖特,F.A. 沃基凯维奇，R.J.H. (2016)肌醇1,4,5-三磷酸受体泛素化. 掠夺. 摩尔. 医学杂志. 反式. Sci. 141, 141-159.
79. 王,我.，史，C.赖特，F.A.郭，D.王，X.王博士.沃基凯维奇，R.J.H. 罗，J. (2017) Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in O瓦里安 Cancer Treatment. 癌症Res. 77, 3293 - 3305.
80. Wojcikiewicz R.J.H. (2018) The making and breaking of inositol 1, 4, 5 - trisphosphate receptor tetramers. 信使 6, 45-49.
81. 赖特,F.A.Bonzerato C.G.斯里尔，D.A. 沃基凯维奇，R.J.H. (2018) The erlin2 T65I mutation inhibits erlin1/2 complex-mediated inositol 1,4,5-trisphosphate受体 ubiquitination and phosphatidylinositol 3-phosphate binding. J. 医学杂志. 化学. 293, 15706-15714.
82. 舒尔曼J.J.斯切斯尼亚克，L.M.邦克，E.N.纳尔逊，H.A.罗伊，M.W.瓦格纳二世，L.A.，圣诞，D.I. 沃基凯维奇，R.J.H. (2019) Bok调节线粒体融合和形态. 细胞死亡和Diff. doi: 10.1038/s41418-019-0327-4.83.
83. 高,X. 沃基凯维奇，R.J.H. (2020) The emerging link between IP3 receptor turnover and Hereditary Spastic Paraplegia. 细胞钙 86:102142. doi: 10.1016/j.盲肠.2019.102142.
84. 盾,Y.李，Y.崔凯.他，M.王，B.巴塔查尔吉，美国.朱，B.， Yago, T.张，K.邓，L.欧阳，K.文，A.考恩，D.B.宋，K.Yu, L.布罗菲，M.L.刘，X.韦利·西尔斯，J.，吴，H.黄，S.崔刚.川岛，Y.松本，H.Kodera, Y.沃基凯维奇，R.J.H.斯里瓦斯塔瓦，S.比肖夫，J.王博士.Z.Ley, K.陈，H. (2020) epsin介导的IP3R1降解促进动脉粥样硬化. Nat. Commun. 11(1):3984. doi: 10.1038/s41467-020-17848-4.
85. Szczesniak L.M.Bonzerato C.G.舒尔曼，J.J.，呸，A. 沃基凯维奇，R.J.H. (2021) Bok binds to a largely disordered loop in the coupling domain of type 1 inositol 1,4,5-trisphosphate受体. 物化学. Biophys. Res Commun. 553, 180-186.
86. Szczesniak L.M.Bonzerato C.G. 沃基凯维奇，R.J.H. (2021)使用接近标记识别Bok相互作用组. 前面. 电池开发. 医学杂志. 9:689951. doi: 10.3389 / fcell.2021.689951.
87. 高,X.Bonzerato C.G. 沃基凯维奇，R.J.H. (2022) erlin1/2复合物与IP的第三个腔内环结合3R1触发泛素蛋白酶体降解. J. 医学杂志. 化学. 298, 102026.
88. Bonzerato C.G.凯勒，K。.R.舒尔曼，J.J.高，X.斯切斯尼亚克，L.M. 沃基凯维奇，R.J.H. (2022) Endogenous Bok is stable at the endoplasmic reticulum and does not mediate proteasome inhibitor-induced apoptosis. 细胞与发育生物学的前沿. 10, 1094302. doi: 10.3389 / fcell.2022.1094302.