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., and Zhang, H . (2023). RNA recruitment switches the fate of protein condensates from autophagic degradation to accumulation. Journal of Cell Biology 222, e202210104.

2. Zheng, Q.X., Chen, Y., Chen, D., Zhao, H.Y., Feng, Y., Meng, Q., Zhao, Y., and Zhang, H. (2022). Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites. Cell 185, 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. and Zhang, H . (2022). Material properties of phase-separated TFEB condensates regulate the autophagy-lysosome pathway. Journal of Cell Biology 221, e202112024.

4. Chen, D., Zheng, Q. X., Sun, L., Ji, M. M., Li, Y., Deng, H. Y., and Zhang, H. (2021). ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress. Developmental Cell 56, 3250-3263.

5. Liu, N., Zhao, H.Y., Zhao, Y.G., Hu, J.J. and Zhang, 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 Biology 220, 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 Cell 56, 427-442.

7. Chen, D., Wang, Z., Zhao, Y.G., Zheng, H., Zhao, H.Y., Liu, N., and Zhang, H. (2020). Inositol polyphosphate multikinase inhibits liquid-liquid phase separation of TFEB to negatively regulate autophagy activity. Developmental Cell 55, 588-602.

8. Miao, G.Y., Zhang, Y.J., Chen, D., and Zhang, H . (2020). The ER-localized transmembrane proteinTMEM39A/SUSR2 regulates autophagy by controlling the trafficking of the PtdIns(4)P phosphatase SAC1. Molecular Cell 77, 618-632.

9. Zhang, Y.J., Qi, L.X., and Zhang, H . (2019). TGFβ-like DAF-7 acts as a systemic signal for autophagy regulation in C. elegans . Journal of Cell Biology 218, 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., and Zhang, H . (2019). The ER-localized protein DFCP1 modulates ER-LD contact formation. Cell Reports 27, 343-358.

11. Zhang, G.M., Wang, Z., Du, Z., and Zhang, H . (2018). mTOR regulates phase separation of PGL granules to modulate their autophagic degradation. Cell 174, 1492-1506.

12. Zhao, Y.G., Liu, N., Miao, G.Y., Chen, Y., Zhao, H.Y, and Zhang, H . (2018). The ER contact proteins VAPA/B interact with multiple autophagy proteins to modulate autophagosome biogenesis. Current Biology 28, 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., and Zhang, H. (2017). The ER-localized transmembrane protein VMP1 regulates SERCA activity to control ER-isolation membrane contacts for autophagosome formation. Molecular Cell 67, 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., and Zhang, H . (2016). The Vici syndrome protein EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. Molecular Cell 63, 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. and Zhang, H . (2015). Structural basis of the differential function of the two C. elegans Atg8 homologs, LGG-1 and LGG-2, in autophagy. Molecular Cell 60, 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., and Zhang, H . (2015). The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis. Autophagy 11, 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., and Zhang, H . (2014). O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation. Nature Cell Biology 16, 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., and Zhang, H . (2014). Genome-wide screen identifies signaling pathways that regulate autophagy during Caenorhabditis elegans development. EMBO reports 15, 705-713.

19. Li, S.H., Yang, P.G., Tian, E, and Zhang, H . (2013). Arginine methylation modulates autophagic degradation of PGL granules in C. elegans . Molecular Cell 52, 421-433.

20. Zhang, P.P., and Zhang, H . (2013). Autophagy modulates miRNA-mediated gene silencing and selectively degrades AIN-1/GW182 in C. elegans . EMBO reports 14, 568-576.

21. Lin, L., Yang, P.G., Huang, X.X., Zhang, H., Lu, Q., and Zhang, H . (2013). The scaffold protein EPG-7 links cargo/receptor complexes with the autophagic assembly machinery. Journal of Cell Biology 201, 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., and Zhang, H. (2013). Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration. Journal of Cell Biology 200, 731-741.

23. Huang, J., Wang, H.B., Chen, Y.Y. Wang, X.X., and Zhang, H . (2012). Residual body removal during spermatogenesis in C. elegans requires genes that mediate cell corpse clearance. Development 139, 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. and Zhang, H . (2011). The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. Developmental Cell 21, 343-357.

25. Huang, X.X., Zhang, H. and Zhang, H . (2011). The zinc-finger protein SEA-2 regulates larval developmental timing and adult life span in C. elegans . Development 138, 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. and Zhang, H . (2010). C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell 141, 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., and Zhang, H . (2009). SEPA-1 mediates the specific recognition and degradation of P granule components by autophagy in C. elegans . Cell 136, 308-321.

28. Yang, Y., Sun, Y.Y., Luo, X., Zhang, Y.X., Chen, Y.Y., Tian, E, Lints, R., and Zhang, H . (2007). Polycomb -like genes are necessary for specification of dopaminergic and serotonergic neurons in Caenorhabditis elegans . PNAS 104, 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., and Zhang, H . (2006). RNA-binding proteins SOP-2 and SOR-1 form a novel PcG-like complex in C. elegans . Development 133, 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 Biology 25, 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., and Zhang, H . (2022). Essence determines phenomenon: Assaying the material properties of biological condensates. Journal of Biological Chemistry 298, 101782.

4. Zhao, Y.G., Codogno, P., and Zhang, H . (2021). Machinery, regulation and pathophysiological implications of autophagosome maturation. Nature Reviews Molecular Cell Biology 22, 733-750.

5. Zhao, Y.G., and Zhang, H . (2020). Phase separation in membrane biology: the interplay between membrane-bound organelles and membraneless condensates. Developmental Cell 55, 30-44.

6. Noda, N.N., Wang, Z., and Zhang, H . (2020). Liquid-liquid phase separation in autophagy. Journal of Cell Biology 219, 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. SCIENCECHINA Life Sciences 63, 953-985.

8. Zhao, Y.G., and Zhang, H . (2019). Core autophagy genes and human diseases. Current Opinion in Cell Biology 61, 117-125.

9. Wang, Z., and Zhang, H . (2019). Phase separation, transition and autophagic degradation of proteins in development and pathogenesis. Trends in Cell Biology 29, 417-427.

10. Zhao, Y.G., and Zhang, H . (2019). Autophagosome maturation: an epic journey from the ER to lysosomes. Journal of Cell Biology 218, 757-770.

11. Zhao, Y.G., and Zhang, H . (2018). Formation and maturation of autophagosomes in higher eukaryotes: a social network. Current Opinion in Cell Biology 53, 29-36.

12. Joshi, A.S., Zhang, H. , and Prinz, W.A. (2017). Organelle biogenesis in the endoplasmic reticulum. Nature Cell Biology 9, 876-882.

13. Zhang, H. , and Baehrecke, E.H. (2015). Eaten alive: novel insights into autophagy from multicellular model systems. Trends in Cell Biology 25, 376-387.

14. Yang, P.G., and Zhang, H . (2014). You are what you eat: multifaceted functions of autophagy during C. elegans development. Cell Research 24, 80-91.

（资料来源：张宏研究员，2025-02-14）