杰出青年科学基金获得者

　　1987 - 1991 安徽大学，本科

　　1991 - 1994 北京大学医学部，硕士

　　1994 - 2001 美国爱因斯坦医学院，博士

　　2001 - 2004 马萨诸塞总医院癌症中心，博士后

　　2004 - 2009 北京生命科学研究所，研究员

　　2009 - 2012 北京生命科学研究所，高级研究员

　　2012 - 至今 中国科学院生物物理研究所，研究员

　　2023年  新基石研究员

　　2022年  中国生命科学十大进展

　　2022年  中源协和生命医学成就奖

　　2020年  第二届全国创新争先奖

　　2019年  国家自然科学奖二等奖

　　2019年  中国细胞生物学学会"杰出成就"奖

　　2018年  臻溪生命学者奖

　　2016年  万人计划

　　2014年  中青年科技创新领军人才

　　2013年  谈家桢生命科学创新奖

　　2012年  国家杰出青年科学基金

　　2012年  霍华德·休斯医学研究所国际青年科学家奖

　　2006年  Lilly亚洲杰出科研成就奖

实验室成员

　　自噬是由自噬体包裹胞质组分并运送到溶酶体降解的过程，对维持细胞正常功能至关重要。自噬异常与多种人类疾病密切相关，如神经退行性疾病等。以往人们对自噬分子机制的理解主要源于对酵母中鉴定的自噬基因的研究。多细胞生物自噬远比酵母自噬复杂，包含多个特有的自噬步骤。我课题组创立了线虫为研究多细胞生物自噬的遗传模型；鉴定了一系列多细胞生物特有的新自噬基因，并揭示了它们在多细胞生物自噬体形成和成熟过程的特有步骤中的作用机制。我课题组最新的研究发现内质网表面钙瞬变是决定自噬起始的关键信号，该发现解决了自噬领域一个长期悬而未决的难题。我们还揭示了液-液相分离在选择性自噬清除蛋白质聚集体中的作用。另外我课题组建立了研究多细胞生物自噬体成熟过程的遗传模型，并阐明了多个调控自噬活性的机理。这些研究极大地丰富了人们对多细胞自噬分子机制和调控机理的认识，并对阐明自噬异常与相关疾病的发病机理及开发新的治疗策略有重要意义。今后实验室将探究自噬起始的调控机制，重点关注内质网表面钙瞬变如何调控自噬体起始位点的组装，并将探讨神经退行性疾病相关基因突变引起的钙动力学异常导致自噬缺陷的机制。

代表性研究论文

1. Zheng, H., Peng, K.F., Gou, X.M., Ju, C., andZhang, H. (2023). RNA recruitment switches the fate of protein condensates from autophagic degradation to accumulation.Journal of Cell Biology222, e202210104.

2. Zheng, Q.X., Chen, Y., Chen, D., Zhao, H.Y., Feng, Y., Meng, Q., Zhao, Y., andZhang, H.(2022). Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites.Cell185, 4082-4098.

3. Wang, Z., Chen, D., Guan, D.S., Liang, X.B., Xue, J.F., Zhao, H.Y., Song, G.T., Lou, J.Z., He, Y. andZhang, H. (2022). Material properties of phase-separated TFEB condensates regulate the autophagy-lysosome pathway.Journal of Cell Biology221, e202112024.

4. Chen, D., Zheng, Q. X., Sun, L., Ji, M. M., Li, Y., Deng, H. Y., andZhang, H.(2021). ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress.Developmental Cell56, 3250-3263.

5. Liu, N., Zhao, H.Y., Zhao, Y.G., Hu, J.J. andZhang, H., (2021). The ER membrane proteins Atlastin 2/3 regulate ER targeting of the ULK1 complex and formation of the ER-isolation membrane contact.Journal of Cell Biology220, e202012091.

6. Miao, G., Zhao, H., Li, Y., Ji, M., Chen, Y., Shi, Y., Bi, Y., Wang, P.,Zhang, H. (2021). ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation,Developmental Cell56, 427-442.

7. Chen, D., Wang, Z., Zhao, Y.G., Zheng, H., Zhao, H.Y., Liu, N., andZhang, H.(2020). Inositol polyphosphate multikinase inhibits liquid-liquid phase separation of TFEB to negatively regulate autophagy activity.Developmental Cell55, 588-602.

8. Miao, G.Y., Zhang, Y.J., Chen, D., andZhang, H. (2020). The ER-localized transmembrane protein TMEM39A/SUSR2 regulates autophagy by controlling the trafficking of the PtdIns(4)P phosphatase SAC1.Molecular Cell77, 618-632.

9. Zhang, Y.J., Qi, L.X., andZhang, H. (2019). TGFβ-like DAF-7 acts as a systemic signal for autophagy regulation inC. elegans.Journal of Cell Biology218, 3998-4006.

10. Li, D.F., Zhao, G.Y., Li, D., Zhao, H.Y., Huang, J., Miao, G.Y., Feng, D., Liu, P.S., Li, D., andZhang, H. (2019). The ER-localized protein DFCP1 modulates ER-LD contact formation.Cell Reports27, 343-358.

11. Zhang, G.M., Wang, Z., Du, Z., andZhang, H. (2018). mTOR regulates phase separation of PGL granules to modulate their autophagic degradation.Cell174, 1492-1506.

12. Zhao, Y.G., Liu, N., Miao, G.Y., Chen, Y., Zhao, H.Y, andZhang, H. (2018). The ER contact proteins VAPA/B interact with multiple autophagy proteins to modulate autophagosome biogenesis.Current Biology28, 1234-1245.

13. Zhao, G.Y., Chen, Y., Miao, G.Y., Zhao, H.Y., Qu, W.Y., Li, D.F., Wang, Z., Liu, N., Li, L., Chen, S., Liu, P.S., Feng, D., andZhang, H.(2017). The ER-localized transmembrane protein VMP1 regulates SERCA activity to control ER-isolation membrane contacts for autophagosome formation.Molecular Cell67, 974-989.

14. Wang, Z., Miao, G.Y., Xue, X., Guo, X.Y., Yuan, C.Z., Wang, Z.Y., Zhang, G.M., Feng, D., Hu, J.J., andZhang, H. (2016). The Vici syndrome protein EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes.Molecular Cell63, 781-795.

15. Wu, F., Watanabe, Y., Guo, X.Y., Qi, X., Wang, P., Zhao, H.Y., Wang, Z., Fujioka, Y., Zhang, H., Ren, J.Q., Fang, T.C., Shen, Y.X., Feng, W., Hu, J.J., Noda, N.N. andZhang, H. (2015). Structural basis of the differential function of the twoC. elegansAtg8 homologs, LGG-1 and LGG-2, in autophagy.Molecular Cell60, 914-929.

16. Zhao, G.Y., Sun, L., Mia, G.Y., Ji, C.C., Zhao, H.Y., Sun, H.Y., Miao, L., Yoshii, S.R., Mizushima, N., Wang X.Q., andZhang, H. (2015). The autophagy geneWdr45/Wipi4regulates learning and memory function and axonal homeostasis.Autophagy11, 881-890.

17. Guo, B., Liang, Q.Q., Li, L., Hu, Z., Wu, F., Zhang, P.P., Ma, Y.F., Zhao, B., Kovács, A.L., Zhang, Z.Y., Feng, D., Chen, S., andZhang, H. (2014). O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation.Nature Cell Biology16, 1215-1226.

18. Guo, B., Huang, X.X., Zhang, P.P., Qi, L.X., Liang, Q.Q., Zhang, X.B., Huang, J., Fang, B., Hou, W.R., Han, J.H., andZhang, H. (2014). Genome-wide screen identifies signaling pathways that regulate autophagy duringCaenorhabditis elegansdevelopment.EMBO reports15, 705-713.

19. Li, S.H., Yang, P.G., Tian, E, andZhang, H. (2013). Arginine methylation modulates autophagic degradation of PGL granules inC. elegans.Molecular Cell52, 421-433.

20. Zhang, P.P., andZhang, H. (2013). Autophagy modulates miRNA-mediated gene silencing and selectively degrades AIN-1/GW182 inC. elegans.EMBO reports14, 568-576.

21. Lin, L., Yang, P.G., Huang, X.X., Zhang, H., Lu, Q., andZhang, H. (2013). The scaffold protein EPG-7 links cargo/receptor complexes with the autophagic assembly machinery.Journal of Cell Biology201, 113-129.

22. Zhao, H.Y., Zhao, G.Y., Wang, X.W., Xu, L.J., Miao, L., Feng, D., Chen, Q., Kovács, A.L. Fan, D.S., andZhang, H.(2013). Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration.Journal of Cell Biology200, 731-741.

23. Huang, J., Wang, H.B., Chen, Y.Y. Wang, X.X., andZhang, H. (2012). Residual body removal during spermatogenesis inC. elegansrequires genes that mediate cell corpse clearance.Development139, 4613-4622.

24. Lu, Q., Yang, P.G., Huang, X.X., Hu, W.Q., Guo, B., Wu, F., Lin, L., Kovács, A.L., Yu, L. andZhang, H. (2011). The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes.Developmental Cell21, 343-357.

25. Huang, X.X., Zhang, H. andZhang, H. (2011). The zinc-finger protein SEA-2 regulates larval developmental timing and adult life span inC. elegans.Development138, 2059-2068.

26. Tian, Y., Li, Z.P., Hu, W.Q., Ren, H.Y., Tian, E, Zhao, Y., Lu, Q., Huang, X.X., Yang, P.G., Li, X., Wang, X.C., Kovács, A.L., Yu, L. andZhang, H. (2010).C. elegansscreen identifies autophagy genes specific to multicellular organisms.Cell141, 1042-1055.

27. Zhang, Y.X., Yan, L.B., Zhou, Z., Yang, P.G., Tian E, Zhang, K., Zhao, Y., Li, Z.P., Song, B., Han, J.H., Miao, L., andZhang, H. (2009). SEPA-1 mediates the specific recognition and degradation of P granule components by autophagy inC. elegans.Cell136, 308-321.　

28. Yang, Y., Sun, Y.Y., Luo, X., Zhang, Y.X., Chen, Y.Y., Tian, E, Lints, R., andZhang, H. (2007).Polycomb-like genes are necessary for specification of dopaminergic and serotonergic neurons inCaenorhabditis elegans.PNAS104, 852-857.

29. Zhang, T.T., Sun Y.Y., Tian, E, Deng, H.S., Zhang, Y.X., Luo, X., Cai, Q.Q., Wang, H., Chai, J.J., andZhang, H. (2006). RNA-binding proteins SOP-2 and SOR-1 form a novel PcG-like complex inC. elegans.Development133, 1023-1033.

代表性综述文章

1. Mayr, C., Mittag,T., Tang, D., Wen, W.Y.,Zhang, H., (co-corresponding) and Zhang, H.Y. (2023). Frontiers in biomolecular condensate research.Nature Cell Biology25, 512-514.

2.Zhang, H. (2022). The genetics of autophagy in multicellular organisms.Annual Review of Genetics. 56, 17-39.

3. Wang, Z., Lou, J.Z., andZhang, H. (2022). Essence determines phenomenon: Assaying the material properties of biological condensates.Journal of Biological Chemistry298, 101782.

4. Zhao, Y.G., Codogno, P., andZhang, H. (2021). Machinery, regulation and pathophysiological implications of autophagosome maturation.Nature Reviews Molecular Cell Biology22, 733-750.

5. Zhao, Y.G., andZhang, H. (2020). Phase separation in membrane biology: the interplay between membrane-bound organelles and membraneless condensates.Developmental Cell55, 30-44.

6. Noda, N.N., Wang, Z., andZhang, H. (2020). Liquid-liquid phase separation in autophagy.Journal of Cell Biology219, e202004062.

7.Zhang, H., Ji, X., Li, P.L., Liu, C., Lou, J.Z., Wang, Z., Wen, W.Y., Xiao, Y., Zhang, M.J. and Zhu, X.L. (2020). Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases.SCIENCE CHINA Life Sciences63, 953-985.

8. Zhao, Y.G., andZhang, H. (2019). Core autophagy genes and human diseases.Current Opinion in Cell Biology61, 117-125.

9. Wang, Z., andZhang, H. (2019). Phase separation, transition and autophagic degradation of proteins in development and pathogenesis.Trends in Cell Biology29, 417-427.

10. Zhao, Y.G., andZhang, H. (2019). Autophagosome maturation: an epic journey from the ER to lysosomes.Journal of Cell Biology218, 757-770.

11. Zhao, Y.G., andZhang, H. (2018). Formation and maturation of autophagosomes in higher eukaryotes: a social network.Current Opinion in Cell Biology53, 29-36.

12. Joshi, A.S.,Zhang, H., and Prinz, W.A. (2017). Organelle biogenesis in the endoplasmic reticulum.Nature Cell Biology9, 876-882.

13.Zhang, H., and Baehrecke, E.H. (2015). Eaten alive: novel insights into autophagy from multicellular model systems.Trends in Cell Biology25, 376-387.

14. Yang, P.G., andZhang, H. (2014). You are what you eat: multifaceted functions of autophagy duringC. elegansdevelopment.Cell Research24, 80-91.

（资料来源：张宏研究员，2023-08-28）