EPG5, tethering autophagosome maturation to Vici syndrome

Hong Zhang
State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
Hong is an investigator at the Institute of Biophysics, Chinese Academy of Sciences, Beijing (March 2012 to present) and was Associate Investigator at the National Institute of Biological Sciences, Beijing and the National Institute of Biological Sciences, Beijing (July 2004 to September 2009). He did his PhD at the Albert Einstein College of Medicine and a Postdoc at the MGH in Boston. Hong is a world leader in the area of C. elegans autophagy, systematically cloning many components involved in this pathway. In the past years he expanded to mammalian systems and human disease mechanisms. Hong attends a meeting in Edinburgh and agreed to come over to Dundee for a day.

Abstract
Autophagy involves the sequestration of a portion of the cytosolic contents in an enclosed double-membrane autophagosomal structure and its subsequent delivery to lysosomes for degradation. The molecular understanding of autophagy has originated almost exclusively from yeast genetic studies. The autophagy process exhibits fundamental differences between yeast and higher eukaryotes, including the presence of steps unique to higher eukaryotes (e.g. autophagosomes maturation). My lab established C. elegans as one of the premier genetic models to study autophagy. Using this model, we carried out the first systematic genetic screens in multicellular organisms and identified a set of metazoan specific autophagy genes, known as epg genes. Among the identified epg genes, we demonstrated that EPG-5 acts a tethering factor that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. Recent studies revealed that EPG5 mutations are causatively linked with the multisystem disorder Vici syndrome. Our study provides insight into the molecular mechanism underlying Vici syndrome.

Publications
Zhang, G.M., Lin, L., Qi, D., and Zhang, H. (2017) The composition of a protein aggregate modulates the specificity and efficiency of its autophagic degradation. Autophagy (in press).
Wang, D., Hou, L., Nakamura, S., Su, M., Li, F., Chen, W., Yan, Y., Green, C.D., Chen, D., Zhang, H., Antebi, A., Han, J.J. (2017) LIN-28 balances longevity and germline stem cell number in Caenorhabditis elegans through let-7/AKT/DAF-16 axis. Aging Cell 16, 113-124.
Miao, G.Y., Zhao, G.Y., Zhao, H.Y., Ji, C.C., Sun, H.Y., Chen, Y.Y., and Zhang, H. (2016) Mice deficient in the Vici syndrome gene Epg5 exhibit features of retinitis pigmentosa. Autophagy 12, 2263-2270.
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. (Recommended in F1000 Prime as being of special significance in its field by F1000 Faculty Member Thierry Galli)
Lu, Q., Yokoyama, C.C., Williams, J.W., Baldridge, M.T., Jin, X.H., DesRochers, B., Bricker, T., Wilen, C.B., Bagaitkar, J. Loginicheva, E., Sergushichev, A, Kreamalmeyer, D., Keller, B.C., Zhao, Y., Kambal, A., Green, D.R., Martinez, J., Dinauer, M.C., Holtzman, M.J., Crouch, E.C., Beatty, W., Boon, A.C.M., Zhang, H., Randolph, G.J., Artyomov, M.N., and Virgin, H.W. (2016) Homeostatic control of innate lung inflammation by Vici syndrome gene Epg5 and additional autophagy genes promotes influenza pathogenesis. Cell Host & Microbe 19, 102-113.
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.
Lin, L., Li, Y.P., Yan. L.B., Zhang. G.M., Zhao, Y., and Zhang, H. (2015) LSY-2 is essential for maintaining the germ-soma distinction in C. elegans. Protein & Cell 6, 599-609.
Na, H., Zhang, P., Chen, Y., Zhu, X., Liu, Y., Liu, Y., Xie, K., Xu, N., Yang, F., Yu, Y., Cichello, S., Mak, H.Y., Wang, M.C., Zhang, H., and Liu, P. (2015) Identification of lipid droplet structure-like/resident proteins in Caenorhabditis elegans. Biochim Biophys Acta. 1853(10 Pt A):2481-91.
Zhao, G.Y., Sun, L., Miao, 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.
Zhang, H., Chang, J.T., Guo, B., Hansen, M., Jia, K.L., Kovács, A.L., Kumsta, C., Lapierre, L.R., Legouis, R., Lin, L., Lu, Q., Meléndez, A., O’Rourke, E.J., Sato, K., Sato, M., Wang, X.C. and Wu, F. (2015) Guidelines for monitoring autophagy in Caenorhabditis elegans. Autophagy 11, 9-27.
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.