真核生物大约三分之一的蛋白在成熟过程中会途经内质网并在其中完成翻译后修饰，获得正确构象，再进一步被运输到合适的地方。内质网为这些蛋白的正确折叠和组装提供了特别的场所，然而基因突变、年龄增长、环境变化等因素可造成内质网功能紊乱、蛋白质折叠受影响（即所谓的“内质网应激”，“ER stress”），进而激活未折叠蛋白响应（Unfolded Protein Response）。未折叠蛋白响应能启动多种反应，包括维持内质网稳态、促进细胞分化、导致细胞凋亡等。非正常的未折叠蛋白响应可以引发诸如神经退行性疾病、糖尿病、癌症等困扰人类的疾病。因此，了解内质网如何发挥正常功能、研究未折叠蛋白响应的发生机制和生理功能可以为我们抵御此类疾病提供科学的依据和有效的手段。

   

071010-生物化学与分子生物学

内质网应激与未折叠蛋白响应及其与疾病的联系

2005-09--2010-06   中国科学院生物物理研究所   博士
2001-09--2005-06   北京师范大学   学士

   

2017-07~现在, 中国科学院生物物理研究所, 研究员
2010-12~2017-06,University of California, San Francisco, Postdoc, Associate Specialist

   

[1] Tao Li, Hongyu Zhao, Gaofeng Guo, Shuwei Xia, Likun Wang. VMP1 affects endoplasmic reticulum stress sensitivity via differential modulation of the three unfolded protein response arms. CELL REPORTS[J]. 2023, 42(3): http://dx.doi.org/10.1016/j.celrep.2023.112209.
[2] Yang, Zaili, Huo, Yazhen, Zhou, Shixin, Guo, Jingya, Ma, Xiaotu, Li, Tao, Fan, Congli, Wang, Likun. Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production. CELL METABOLISM[J]. 2022, 34(12): 2018-+, http://dx.doi.org/10.1016/j.cmet.2022.10.010.
[3] 王立堃. 内质网应激下的内质网-线粒体互作. 中国科学:生命科学[J]. 2022, 52(1): 46-57, http://lib.cqvip.com/Qikan/Article/Detail?id=7106602400.
[4] Yu, Jiaojiao, Li, Tao, Liu, Yu, Wang, Xi, Zhang, Jianchao, Wang, Xie, Shi, Guizhi, Lou, Jizhong, Wang, Likun, Wang, Chihchen, VVang, Lei. Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress. EMBO JOURNAL[J]. 2020, 39(10): e103841-, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232009/.
[5] 田烨, 王立堃. 跨细胞蛋白质内稳态调控机制. 中国基础科学[J]. 2018, 20(3): 4-7, http://lib.cqvip.com/Qikan/Article/Detail?id=676330461.
[6] Morita, Shuhei, Villalta, S Armando, Feldman, Hannah C, Register, Ames C, Rosenthal, Wendy, HoffmannPetersen, Ingeborg T, Mehdizadeh, Morvarid, Ghosh, Rajarshi, Wang, Likun, ColonNegron, Kevin, MezaAcevedo, Rosa, Backes, Bradley J, Maly, Dustin J, Bluestone, Jeffrey A, Papa, Feroz R. Targeting ABL-IRE1 alpha Signaling Spares ER- Stressed Pancreatic beta Cells to Reverse Autoimmune Diabetes. CELL METABOLISM[J]. 2017, 25(4): 883-+, [7] Morita Shuhei, Villalta S Armando, Feldman Hannah C, Register Ames C, Rosenthal Wendy, HoffmannPetersen Ingeborg T, Mehdizadeh Morvarid, Ghosh Rajarshi, Wang Likun, ColonNegron Kevin, MezaAcevedo Rosa, Backes Bradley J, Maly Dustin J, Bluestone Jeffrey A, Papa Feroz R. Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes. CELL METABOLISM[J]. 2017, 25(5): 1207-1207, http://dx.doi.org/10.1016/j.cmet.2017.03.018.
[8] Feldman Hannah C, Tong Michael, Wang Likun, MezaAcevedo Rosa, Gobillot Theodore A, Lebedev Ivan, Gliedt Micah J, Hari Sanjay B, Mitra Arinjay K, Backes Bradley J, Papa Feroz R, Seeliger Markus A, Maly Dustin J. Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands. ACSCHEMICALBIOLOGY[J]. 2016, [9] Feldman, Hannah C, Tong, Michael, Wang, Likun, MezaAcevedo, Rosa, Gobillot, Theodore A, Lebedev, Ivan, Gliedt, Micah J, Hari, Sanjay B, Mitra, Arinjay K, Backes, Bradley J, Papa, Feroz R, Seeliger, Markus A, Maly, Dustin J. Structural and Functional Analysis of the Allosteric Inhibition of IRE1 alpha with ATP-Competitive Ligands. ACS CHEMICAL BIOLOGY[J]. 2016, 11(8): 2195-2205, https://www.webofscience.com/wos/woscc/full-record/WOS:000381847700015.
[10] Ghosh, Rajarshi, Wang, Likun, Wang, Eric S, Perera, B Gayani K, Igbaria, Aeid, Morita, Shuhei, Prado, Kris, Thamsen, Maike, Caswell, Deborah, Macias, Hector, Weiberth, Kurt F, Gliedt, Micah J, Alavi, Marcel V, Hari, Sanjay B, Mitra, Arinjay K, Bhhatarai, Barun, Schuerer, Stephan C, Snapp, Erik L, Gould, Douglas B, German, Michael S, Backes, Bradley J, Maly, Dustin J, Oakes, Scott A, Papa, Feroz R. Allosteric Inhibition of the IRE1 alpha RNase Preserves Cell Viability and Function during Endoplasmic Reticulum Stress. CELL[J]. 2014, 158(3): 534-548, https://www.webofscience.com/wos/woscc/full-record/WOS:000340944300008.
[11] Wang Likun. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nature Chemical Biololy. Nature Chemical Biology. 2012, [12] Wang Likun. IRE1α Cleaves Select microRNAs during ER Stress to Derepress Translation of Pro-apoptotic Caspase-2. SCIENCE. 2012, [13] Wang, Xi, Wang, Likun, Wang, Xie, Sun, Fei, Wang, Chihchen. Structural insights into the peroxidase activity and inactivation of human peroxiredoxin 4. BIOCHEMICAL JOURNAL[J]. 2012, 441: 113-118, http://dx.doi.org/10.1042/BJ20110380.
[14] Wang, Likun, Perera, B Gayani K, Hari, Sanjay B, Bhhatarai, Barun, Backes, Bradley J, Seeliger, Markus A, Schuerer, Stephan C, Oakes, Scott A, Papa, Feroz R, Maly, Dustin J. Divergent allosteric control of the IRE1 alpha endoribonuclease using kinase inhibitors. NATURE CHEMICAL BIOLOGY[J]. 2012, 8(12): 982-989, https://www.webofscience.com/wos/woscc/full-record/WOS:000311491200013.
[15] Pan, Congyan, Zheng, Ji, Wu, Yanyun, Chen, Yingxiao, Wang, Likun, Zhou, Zhansong, Yin, Wenxuan, Ji, Guangju. ERp44 C160S/C212S mutants regulate IP3R1 channel activity. PROTEIN & CELL[J]. 2011, 2(12): 990-996, https://www.webofscience.com/wos/woscc/full-record/WOS:000310522900007.
[16] Wang, Likun, Wang, Lei, Vavassori, Stefano, Li, Shengjian, Ke, Huimin, Anelli, Tiziana, Degano, Massimo, Ronzoni, Riccardo, Sitia, Roberto, Sun, Fei, Wang, Chihchen. Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail. EMBO REPORTS[J]. 2008, 9(7): 642-647, http://www.irgrid.ac.cn/handle/1471x/757645.

   

（ 1 ） 内质网应激下IRE1alpha活性调控机制研究, 主持, 国家级, 2018-01--2021-12
（ 2 ） 内质网-线粒体互作对未折叠蛋白响应的调节及其生理意义, 主持, 国家级, 2018-01--2020-12
（ 3 ） 跨细胞蛋白质内稳态调控机制, 参与, 国家级, 2017-07--2022-06

现指导学生

陈思  硕士研究生  071010-生物化学与分子生物学  

杨再立  博士研究生  071010-生物化学与分子生物学  

李桃  博士研究生  071010-生物化学与分子生物学