研究工作：
蛋白質積聚和募集作用、細胞效應與細胞穩態的分子機制及與神經退行性疾病的關系。
關鍵詞：
蛋白質積聚，包涵體、募集作用、相互作用、相變，蛋白質穩態平衡，蛋白質病理;
細胞穩態，分子伴侶、泛素-蛋白酶體、蛋白質降解， RNA-結合蛋白、RNA穩態平衡，功能喪失、細胞毒性、神經退行性;
細胞生物化學，生物化學技術、生物物理技術、核磁共振、熒光、免疫熒光顯微鏡技術。
神經退行性疾病(如帕金森癥)的發生與神經細胞內的蛋白質的錯誤折疊、異常淀粉樣積聚和包涵體形成有關。本課題組著重研究神經退行性疾病相關蛋白質積聚、募集作用、相變和細胞內蛋白質穩態平衡調節的分子機制。在結構信息基礎上，結合現代生命科學的研究成果理解細胞內蛋白質錯誤折疊、淀粉樣化積聚和穩態平衡調節的細胞效應及與神經退行性疾病發生的聯系。
課題組將結合生物化學、分子生物學、結構生物學和細胞生物學的原理和方法研究蛋白質的錯誤折疊和積聚的分子機制及與神經退行性疾病發生的聯系。將以神經退行性疾病相關的PolyQ蛋白質和RNA-結合蛋白質為對象，研究蛋白質的錯誤折疊、積聚和包涵體形成，分子伴侶和輔伴侶的作用，以及細胞內蛋白質的穩態平衡調節過程。課題組重點關注的科學問題是：蛋白質為什么會發生錯誤折疊和積聚; 蛋白質錯誤折疊和積聚有什么細胞效應; 以及細胞是如何清除蛋白質積聚物或包涵體的。我們目前感興趣的主要研究方向：
(1) 神經退行性疾病相關蛋白質的結構轉換、淀粉樣積聚和分子識別的機制;
(2) 蛋白質積聚所形成的包涵體對細胞內相互作用蛋白質的募集作用;
(3) 神經退行性疾病相關的細胞內蛋白質穩態平衡和質量控制;
(4) 蛋白質穩態平衡和質量控制中蛋白質相互作用和分子識別的NMR結構基礎及生物功能詮釋。
代表論著：
課題組已在J Biol Chem, FASEB J, Structure, JACS, Science等國際刊物上發表研究論文九十多篇，下列為代表性論文：
- 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.
- 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.
- 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.
- [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.
- 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.
- 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.
- 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.
- 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 P97UFD1/NPL4 complex. J Biol Chem, 2013, 288(43):31339-31349.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
