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　　蛋白質(zhì)積聚和募集作用、細(xì)胞效應(yīng)與細(xì)胞穩(wěn)態(tài)的分子機(jī)制及與神經(jīng)退行性疾病的關(guān)系。

　　關(guān)鍵詞：

　　蛋白質(zhì)積聚，包涵體、募集作用、相互作用、相變，蛋白質(zhì)穩(wěn)態(tài)平衡，蛋白質(zhì)病理;

　　細(xì)胞穩(wěn)態(tài)，分子伴侶、泛素-蛋白酶體、蛋白質(zhì)降解， RNA-結(jié)合蛋白、RNA穩(wěn)態(tài)平衡，功能喪失、細(xì)胞毒性、神經(jīng)退行性;

　　細(xì)胞生物化學(xué)，生物化學(xué)技術(shù)、生物物理技術(shù)、核磁共振、熒光、免疫熒光顯微鏡技術(shù)。

　　神經(jīng)退行性疾病(如帕金森癥)的發(fā)生與神經(jīng)細(xì)胞內(nèi)的蛋白質(zhì)的錯(cuò)誤折疊、異常淀粉樣積聚和包涵體形成有關(guān)。本課題組著重研究神經(jīng)退行性疾病相關(guān)蛋白質(zhì)積聚、募集作用、相變和細(xì)胞內(nèi)蛋白質(zhì)穩(wěn)態(tài)平衡調(diào)節(jié)的分子機(jī)制。在結(jié)構(gòu)信息基礎(chǔ)上，結(jié)合現(xiàn)代生命科學(xué)的研究成果理解細(xì)胞內(nèi)蛋白質(zhì)錯(cuò)誤折疊、淀粉樣化積聚和穩(wěn)態(tài)平衡調(diào)節(jié)的細(xì)胞效應(yīng)及與神經(jīng)退行性疾病發(fā)生的聯(lián)系。

　　課題組將結(jié)合生物化學(xué)、分子生物學(xué)、結(jié)構(gòu)生物學(xué)和細(xì)胞生物學(xué)的原理和方法研究蛋白質(zhì)的錯(cuò)誤折疊和積聚的分子機(jī)制及與神經(jīng)退行性疾病發(fā)生的聯(lián)系。將以神經(jīng)退行性疾病相關(guān)的PolyQ蛋白質(zhì)和RNA-結(jié)合蛋白質(zhì)為對(duì)象，研究蛋白質(zhì)的錯(cuò)誤折疊、積聚和包涵體形成，分子伴侶和輔伴侶的作用，以及細(xì)胞內(nèi)蛋白質(zhì)的穩(wěn)態(tài)平衡調(diào)節(jié)過(guò)程。課題組重點(diǎn)關(guān)注的科學(xué)問(wèn)題是：蛋白質(zhì)為什么會(huì)發(fā)生錯(cuò)誤折疊和積聚; 蛋白質(zhì)錯(cuò)誤折疊和積聚有什么細(xì)胞效應(yīng); 以及細(xì)胞是如何清除蛋白質(zhì)積聚物或包涵體的。我們目前感興趣的主要研究方向：

　　(1) 神經(jīng)退行性疾病相關(guān)蛋白質(zhì)的結(jié)構(gòu)轉(zhuǎn)換、淀粉樣積聚和分子識(shí)別的機(jī)制;

　　(2) 蛋白質(zhì)積聚所形成的包涵體對(duì)細(xì)胞內(nèi)相互作用蛋白質(zhì)的募集作用;

　　(3) 神經(jīng)退行性疾病相關(guān)的細(xì)胞內(nèi)蛋白質(zhì)穩(wěn)態(tài)平衡和質(zhì)量控制;

　　(4) 蛋白質(zhì)穩(wěn)態(tài)平衡和質(zhì)量控制中蛋白質(zhì)相互作用和分子識(shí)別的NMR結(jié)構(gòu)基礎(chǔ)及生物功能詮釋。

　　課題組已在J Biol Chem, FASEB J, Structure, JACS, Science等國(guó)際刊物上發(fā)表研究論文九十多篇，下列為代表性論文：

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.