Hong Zhang, Ph.D.

Associate Investigator, NIBS, Beijing, China

Education

Professional Experience:

Research Description

Autophagy, an evolutionarily conserved intracellular catabolic process, involves formation of a double membrane structure, called the autophagosome, which engulfs portions of the cytosol and delivers them to lysosomes for degradation. In higher eukaryotes, autophagy is important for diverse processes, such as adaptation to starvation and stress, removal of aggregate-prone proteins and elimination of pathogens. Deregulated autophagy has been linked to pathologic conditions such as neurodegeneration, cardiomyopathy and tumor progression. Studies of autophagy in higher eukaryotes are greatly facilitated by the functional conservation of yeast Atg proteins. However, autophagy in higher eukaryotes involves much more complex membrane dynamics. Thus, it is conceivable that the higher eukaryote autophagy pathway might require more elaborate molecular machinery, including factors that are absent in yeast. So far, very little is known about higher eukaryote-specific autophagy components.

We demonstrated that autophagy is required for degradation of several aggregate prone proteins during C. elegansembryogenesis, including germline P granule components in somatic cells. We further performed genetic screens to isolate mutants with defective degradation of autophagy substrates and identified four previously uncharacterized, higher eukaryote-specific autophagy genes, epg-2, -3, -4 and -5, which define discrete genetic steps in the autophagy pathway. Our study establishes C. elegans as a multicellular genetic model to delineate the autophagy pathway. Our findings using this system provide a genetic framework for further study of basal and selective autophagic degradation of protein aggregates in mammalian cells.

Research Description

Autophagy, an evolutionarily conserved intracellular catabolic process, involves formation of a double membrane structure, called the autophagosome, which engulfs portions of the cytosol and delivers them to lysosomes for degradation. In higher eukaryotes, autophagy is important for diverse processes, such as adaptation to starvation and stress, removal of aggregate-prone proteins and elimination of pathogens. Deregulated autophagy has been linked to pathologic conditions such as neurodegeneration, cardiomyopathy and tumor progression. Studies of autophagy in higher eukaryotes are greatly facilitated by the functional conservation of yeast Atg proteins. However, autophagy in higher eukaryotes involves much more complex membrane dynamics. Thus, it is conceivable that the higher eukaryote autophagy pathway might require more elaborate molecular machinery, including factors that are absent in yeast. So far, very little is known about higher eukaryote-specific autophagy components.

We demonstrated that autophagy is required for degradation of several aggregate prone proteins during C. elegans embryogenesis, including germline P granule components in somatic cells. We further performed genetic screens to isolate mutants with defective degradation of autophagy substrates and identified four previously uncharacterized, higher eukaryote-specific autophagy genes, epg-2, -3, -4 and -5, which define discrete genetic steps in the autophagy pathway. Our study establishes C. elegans as a multicellular genetic model to delineate the autophagy pathway. Our findings using this system provide a genetic framework for further study of basal and selective autophagic degradation of protein aggregates in mammalian cells.

Publications:

1. 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 (in press).

2. Yang, P.G. and Zhang, H. (2011) The coiled-coil domain protein EPG-8 plays an essential role in the autophagy pathway in C. elegans. Autophagy 7, 159-165.

3. Ren, H.Y. and Zhang, H. (2010) Wnt signaling controls temporal identities of seam cells in Caenorhabditis elegans. Developmental Biology 345, 144-155.

4. 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 multi-cellular organisms. Cell 141, 1042-55.

5. Kovács, A.L, and Zhang, H. (2010) Role of autophagy in Caenorhabditis elegans. FEBS Lett. 584, 1335-41.

6. Huang, X.X., Tian, E, Xu, Y.H., and Zhang, H. (2009) The C. elegans engrailed homologceh-16 regulates the self-renewal expansion division of stem cell-like seam cells.Developmental Biology 333, 337-347.

7. Xia, D., Huang, X.X., and Zhang, H. (2009) The temporally regulated transcription factor sel-7 controls the developmental timing in C. elegans. Developmental Biology332, 246-257.

8. Tian, E, Wang, F.X., Han, J.H., and Zhang, H. (2009) epg-1 functions in the autophagy pathway and may encode a highly divergent Atg13 homolog in C. elegans.Autophagy 5, 608-615.

9. Zhao, Y., Tian, E, and Zhang, H. (2009) Selective autophagic degradation of maternally loaded germline P granule components in somatic cells during C. elegansembryogenesis. Autophagy 5, 717-719.

10. 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.

11. Cai, Q.C., Sun, Y.Y., Huang, X.X., Guo, C., Zhang, Y.X., Chen, Y.Y., and Zhang, H.(2008) The C. elegans PcG-like gene sop-2 coordinately regulates the temporal, spatial, and sexual specificities of cell fates. Genetics 178, 1445-1456.

12. Deng, H., Xia, D., Fang, B., and Zhang, H. (2007) The Flightless I homolog, fli-1,regulates anterior-posterior polarity, asymmetric cell division and ovulation during C. elegans development. Genetics 177, 847-860.

13. Xia, D., Zhang, Y.X., Huang, X.X., Sun, Y.Y., and Zhang, H. (2007) The C. elegansbCBF homolog, BRO-1, regulates the proliferation, differentiation and specification of the stem cell-like seam cell lineages. Developmental Biology 309, 259-272.

14. Deng, H., Sun, Y.Y, Zhang, Y.X., Luo, X., Hou, W.R., Tian, E, Han, J.H., and Zhang, H.(2007) The C. elegans NF-Y complex functions as PcG proteins in Hox gene repression. Developmental Biology 308, 583-592.

15. 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.

16. Zhang, T., Sun, Y., Tian, E, Deng, H., Zhang, Y., Luo, X., Cai, Q., Wang, H., Chai, 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.

17. Sun, Y., and Zhang, H. (2005) A Unified Mode of Epigenetic Gene Silencing: RNA Meets Polycomb Group Proteins. RNA biology 2, 8-10.

18. Zhang, H., Christoforou, A., Aravind, L., Emmons, S.W., van den Heuvel, S., and Haber, D.A. (2004) The C. elegans Polycomb gene sop-2 encodes an RNA binding protein. Molecular Cell 14, 841-847.

19. Zhang, H., Smolen, G., Palmer, R., Christoforou, A., van den Heuvel, S., and Haber, D.A. (2004) SUMO modification is required for in vivo Hox gene regulation by the C. elegans Polycomb group protein SOP-2. Nature Genetics 36, 507-511.

20. Zhang, H., Palmer, R., Gao, X., Kreidberg, J., Gerald, W., Hsiao, L., Jensen, R.V., Gullans, S.R., and Haber, D.A. (2003) Transcriptional Activation of Placental Growth Factor by the Forkhead/Winged Helix Transcription Factor FoxD1. Current Biology 13, 1625-1629.

21. Zhang, H., Azevedo, R.B., Lints, R., Doyle, C., Teng, Y., Haber, D., and Emmons, S.W. (2003) Global regulation of Hox gene expression in C. elegans by a SAM domain protein. Developmental Cell 4, 903-915.

22. Zhang H., and Emmons S.W. (2002) C. elegans unc-37/groucho interacts genetically with components of the transcriptional mediator complex. Genetics 160, 799-803.

23. Zhang, H., and Emmons S.W. (2001) The novel C. elegans gene sop-3 modulates the Wnt signaling to regulate the expression and function of Hox genes. Development128, 767-777.

24. Zhang, H., and Emmons, S.W. (2000) A C. elegans mediator protein confers regulatory stringency on lineage-specific expression of a transcription factor gene.Genes & Development 14, 2161-2172.

Invited review:

Tian, Y., Ren, H.Y., Zhao, Y., Lu, Q., Huang, X.X., Yang, P.G., and Zhang, H. (2010)Four metazoan autophagy genes regulate cargo recognition, autophagosome formation and autolysosomal degradation. Autophagy 6, 984-985.

Kovács, A.L. and Zhang, H. (2010) Role of autophagy in Caenorhabditis elegans. FEBS letters 584, 1335-1341.

Sun, Y.Y. and Zhang, H. (2005) A Unified Mode of Epigenetic Gene Silencing: RNA Meets Polycomb Group Proteins. RNA biology 2, 8-10.