Professor of Cellular & Molecular Medicine
Ph.D., UC Berkeley
We are determining how organelles are inherited and how they maintain their identity in both yeast and mammals. Ras-like GTPases (called Rabs) interact in a signal cascade that regulates the flow of membrane traffic. Rabs are molecular switches that are active in their GTP-bound form and inactive when bound to GDP. Using GFP tagged proteins and microscopy, we are visualizing how organelles are formed and transferred from mother to daughter cells. In yeast, we are using mutational analysis to isolate mutants that disrupt these cellular events. This approach has led to the identification of membrane proteins and novel complexes as key players in these processes. In vitro assays are also being used to reconstitute these events at a biochemical level.
The TRAPP complexes are multimeric guanine nucleotide exchange factors (GEF) that activate the GTPase Rab1. A focus of our studies is to understand the role of Rab1, which has been implicated in neurodegenerative diseases such as Parkinson’s. TRAPP requires four subunits (Bet3, Bet5, Trs23 and Trs31) for its GEF activity. How each of these subunits contributes to this activity has recently been defined. The smaller TRAPP complex, TRAPPI, specifically binds to ER-derived vesicles and tethers them to their acceptor compartment. The larger complex, TRAPPII, is a Rab1 GEF that contains adaptor subunits which tether it to an early Golgi compartment. Recently, a third TRAPP complex has been implicated in autophagy, a catabolic process that targets the degradation of proteins and organelles for lysosomal degradation. Understanding the mechanism of autophagy is important for the study of cancer and certain neurological diseases
Key words: protein traffic, autophagy, human disease, Rab, organelle inheritance
Model systems: humans and yeast
Wang, J., Menon, S., Yamasaki, A., Chou, H.-T., Walz, T., Jiang, Y. and Ferro-Novick, S. 2013. Ypt1 recruits the Atg1 kinase to the preautophagosomal structure. PNAS 110:9800-9805.
Chen, S., Novick, P. and Ferro-Novick, S. 2012. ER network formation requires a balance of the dynamin-like GTPase Sey1 and the Lunapark family member Lnp1p. Nature Cell Biol 14:707-716.
Lord, C., Bhandari, D., Menon, S., Ghassemian, M., Nycz, D., Hay, J., Ghosh, P., and Ferro-Novick, S. 2011. Sequential interactions with Sec23 control the direction of vesicle traffic. Nature 473: 181-186.
Barrowman, J., Bhandari, D., Reinisch, K. and Ferro-Novick, S. 2010. TRAPP complexes in membrane traffic: convergence through a common Rab. Nat Rev Mol. Cell 11: 759-763.
Lynch-Day, M.A., Bhandari, D., Menon, S. Huang, J., Cai, H., Bartholomew, C.R., Brummell, J.H., Ferro-Novick, S. * and Klionsky, D.J.*. 2010. Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy. PNAS 107: 7811-7816. (*co-corresponding senior authors)
Yamasaki, A., Menon, S., Yu, S., Barrowman, J., Meerloo, T., Oorschot, V., Klumperman, J., Satoh, A. and Ferro-Novick, S. 2009. mTrs130 is a component of a mammalian TRAPPII complex, a Rab1 GEF that binds to COPI coated vesicles, Mol. Biol. Cell 20, 4205-4215.
Cai, Y., Chin, H., Lazarova, D., Menon, S., Fu, C., Cai, H., Sclafani, A., Rodgers, D.W., De La Cruz, E., Ferro-Novick, S. *, and Reinisch, K* (2008). The structural basis for activation of the Rab Ypt1p by the TRAPP membrane tethering complexes. Cell 133, 1202-1213. (*co-corresponding senior authors)
Cai, H., Yu, S., Menon, S., Cai, Y., Lazarova, D., Fu, C., Reinisch, K., Hay, J. C. and Ferro-Novick, S. (2007). TRAPPI tethers COPII vesicles by binding the coat subunit Sec23p. Nature 445, 941-944.
Cai, H., Reinisch, K., and Ferro-Novick, S. (2007). Coats, Tethers, Rabs and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev Cell 12, 671-682.