蛋白质积聚和募集作用、细胞效应与细胞稳态的分子机制及与神经退行性疾病的关系。

　　关键词：

　　蛋白质积聚，包涵体、募集作用、相互作用、相变，蛋白质稳态平衡，蛋白质病理;

　　细胞稳态，分子伴侣、泛素-蛋白酶体、蛋白质降解， RNA-结合蛋白、RNA稳态平衡，功能丧失、细胞毒性、神经退行性;

　　细胞生物化学，生物化学技术、生物物理技术、核磁共振、荧光、免疫荧光显微镜技术。

　　神经退行性疾病(如帕金森症)的发生与神经细胞内的蛋白质的错误折叠、异常淀粉样积聚和包涵体形成有关。本课题组着重研究神经退行性疾病相关蛋白质积聚、募集作用、相变和细胞内蛋白质稳态平衡调节的分子机制。在结构信息基础上，结合现代生命科学的研究成果理解细胞内蛋白质错误折叠、淀粉样化积聚和稳态平衡调节的细胞效应及与神经退行性疾病发生的联系。

　　课题组将结合生物化学、分子生物学、结构生物学和细胞生物学的原理和方法研究蛋白质的错误折叠和积聚的分子机制及与神经退行性疾病发生的联系。将以神经退行性疾病相关的PolyQ蛋白质和RNA-结合蛋白质为对象，研究蛋白质的错误折叠、积聚和包涵体形成，分子伴侣和辅伴侣的作用，以及细胞内蛋白质的稳态平衡调节过程。课题组重点关注的科学问题是：蛋白质为什么会发生错误折叠和积聚; 蛋白质错误折叠和积聚有什么细胞效应; 以及细胞是如何清除蛋白质积聚物或包涵体的。我们目前感兴趣的主要研究方向：

　　(1) 神经退行性疾病相关蛋白质的结构转换、淀粉样积聚和分子识别的机制;

　　(2) 蛋白质积聚所形成的包涵体对细胞内相互作用蛋白质的募集作用;

　　(3) 神经退行性疾病相关的细胞内蛋白质稳态平衡和质量控制;

　　(4) 蛋白质稳态平衡和质量控制中蛋白质相互作用和分子识别的NMR结构基础及生物功能诠释。

　　课题组已在J Biol Chem, FASEB J, Structure, JACS, Science等国际刊物上发表研究论文九十多篇，下列为代表性论文：

1. Wei Xue^#, Shu-Xian Zhang^#, Wen-Tian He, Jun-Ye Hong, Lei-Lei Jiang, and Hong-Yu Hu^*, Domain interactions reveal auto-inhibition of the deubiquitinating enzyme USP19 and its activation by HSP90 in the modulation of huntingtin aggregation. Biochem J, 2020, 477(21): 4295–4312.
2. Xiao-feng Zhuo, Jian Wang, Jing Zhang, Lei-lei Jiang, Hong-Yu Hu*, and Jun-xia Lu*, Solid-State NMR Reveals the Structural Transformation of the TDP-43 Amyloidogenic Region upon Fibrillation. JACS, 2020, 142(7): 3412-3421.
3. Hui Yang^#, Hong-Wei Yue^#, Wen-Tian He, Jun-Ye Hong, Lei-Lei Jiang, and Hong-Yu Hu*, PolyQ-expanded huntingtin and ataxin-3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin. FASEB J, 2018, 32 (6): 2923-2933.
4. [R] Hui Yang and Hong-Yu Hu*, Sequestration of cellular interacting partners by protein aggregates: implication in a loss-of-function pathology. FEBS J, 2016, 283: 3705-3717.
5. Hui Yang, Shuai Liu, Wen-Tian He, Jian Zhao, Lei-Lei Jiang and Hong-Yu Hu*, Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5- Acetyltransferase (SAGA) Complex. J Biol Chem, 2015, 290(36): 21996-22004.
6. Hui Yang, Jing-Jing Li, Shuai Liu, Jian Zhao, Ya-Jun Jiang, Ai-Xin Song, and Hong-Yu Hu*, Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology. Sci Rep, 2014, 4: 6410.
7. Yong-Guang Gao^*, Hui Yang, Jian Zhao, Ya-Jun Jiang, and Hong-Yu Hu*, Autoinhibitory Structure of the WW Domain of HYPB/SETD2 Regulates Its Interaction with the Proline-Rich Region of Huntingtin. Structure, 2014, 22(3): 378-386.
8. Shuai Liu, Hui Yang, Yu-Hang Zhang, Ai-Xin Song, and Hong-Yu Hu*, NEDD8 ultimate buster-1 long (NUB1L) protein promotes transfer of NEDD8 to proteasome for degradation through the P97^UFD1/NPL4 complex. J Biol Chem, 2013, 288(43):31339-31349.
9. Lei-Lei Jiang, Mei-Xia Che, Jian Zhao, Chen-Jie Zhou, Mu-Yun Xie, Hai-Yin Li, Jian-Hua He and Hong-Yu Hu*, Structural Transformation of the Amyloidogenic Core Region of TAR DNA Binding Protein of 43 kDa (TDP-43) Initiates Its Aggregation and Cytoplasmic Inclusion. J Biol Chem, 2013, 288(27): 19614-19624.
10. Xue-Chao Gao, Chen-Jie Zhou, Zi-Ren Zhou, Meng Wu, Chun-Yang Cao and Hong- Yu Hu*, The C-terminal Helices of Heat Shock Protein 70 Are Essential for J-domain Binding and ATPase Activation. J Biol Chem, 2012, 287(8): 6044-6052.
11. Ya-Jun Jiang, Mei-Xia Che, Jin-Qiao Yuan, Yuan-Yuan Xie, Xian-Zhong Yan, and Hong-Yu Hu*, Interaction with Polyglutamine Expanded Huntingtin Alters Cellular Distribution and RNA Processing of Huntingtin Yeast Two-hybrid Protein A (HYPA). J Biol Chem, 2011, 286 (28): 25236-25245.
12. Mei-Xia Che, Ya-Jun Jiang, Yuan-Yuan Xie, Lei-Lei Jiang and Hong-Yu Hu*, Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing. FASEB J, 2011, 25 (7): 2344-2353.
13. Xiao-Wei Zhang, Xiao-Jing Yan, Zi-Ren Zhou, Fei-Fei Yang, Zi-Yu Wu,^，Hong-Bin Sun, Wen-Xue Liang, Ai-Xing Song, Lallemand-Breitenbach Valerie, Jeanne Marion, Qun-Ye Zhang, Huai-Yu Yang, Qiu-Hua Huang, Guang-Biao Zhou, Jian-Hua Tong, Yan Zhang, Ji-Hui Wu, Hong-Yu Hu, Hugues de Thé, Sai-Juan Chen*, Zhu Chen*, The Leukemia Drug Arsenic Trioxide Controls the Fate of the PML-RARa Oncoprotein by Directly Binding PML. Science, 2010, 328: 240-243.
14. Yuan-Yuan Xie, Chen-Jie Zhou, Zi-Ren Zhou, Jing Hong, Mei-Xia Che, Qing-Shan Fu, Ai-Xin Song, Dong-Hai Lin, and Hong-Yu Hu*, Interaction with synphilin-1 promotes inclusion formation of a-synuclein: Mechanistic insights and pathological implication. FASEB J, 2010, 24 (1): 196-205.
15. Qing-Shan Fu, Chen-Jie Zhou, Hong-Chang Gao, Ya-Jun Jiang, Zi-Ren Zhou, Jing Hong, Wen-Ming Yao, Ai-Xin Song, Dong-Hai Lin*, andHong-Yu Hu*, Structural Basis for Ubiquitin Recognition by a Novel Domain from Human Phospholipase A2 Activating Protein. J Biol Chem, 2009, 284 (28): 19043-19052.
16. Yong-Gang Chang, Xian-Zhong Yan, Yuan-Yuan Xie, Xue-Chao Gao, Ai-Xin Song, Dong-Er Zhang and Hong-Yu Hu*, Different Roles for Two Ubiquitin-like Domains of ISG15 in Protein Modification. J Biol Chem, 2008, 283 (19): 13370-13377.
17. Yong-Guang Gao, Xian-Zhong Yan*, Ai-Xin Song, Yong-Gang Chang, Xue-Chao Gao, Nan Jiang, Qi Zhang, and Hong-Yu Hu*, Structural insights into the specific binding of huntingtin proline-rich region with SH3 and WW domains. Structure, 2006, 14 (12): 1755-1765.
18. Hong-Tao Li, Dong-Hai Lin, Xiao-Ying Luo, Feng Zhang, Li-Na Ji, Hai-Ning Du, Guo-Qiang Song, Jun Hu, Jia-Wei Zhou and Hong-Yu Hu*. Inhibition of α-synuclein fibrillization by dopamine analogs via reaction with the amino groups of α-synuclein: Implication for dopaminergic neurodegeneration. FEBS J, 2005, 272 (14): 3661-3672.
19. Hong-Yu Hu, Julie K. Horton, Michael R. Gryk, Rajendra Prasad, Jana M Naron, Di-An Sun, Sidney M. Hecht, Samuel H. Wilson*, Gregory P Mullen, Identification of small molecule synthetic inhibitors of DNA polymerase beta by NMR chemical shift mapping. J Biol Chem, 2004, 279 (38): 39736-39744.
20. Hai-Ning Du, Lin Tang, Xiao-Ying Luo, Hong-Tao Li, Jun Hu, Jia-Wei Zhou, and Hong-Yu Hu*, A peptide motif consisting of glycine, alanine and valine is required for fibrillization and cytotoxicity of human a-synuclein. Biochemistry, 2003, 42 (29): 8870-8878.