Susan Ferro-Novick, Ph.D.

Professor of Cell Biology Investigator, Howard Hughes Medical Institute
Phone: (203) 737-5207 Lab: (203) 737-4453/-4451 Fax: (203) 737-5246 e-mail: susan.ferronovick@yale.edu		Department of Cell Biology Yale Universtiy School of Medicine 333 Cedar Street PO Box 208002 New Haven, CT 06520-8002 <Courier Address> 295 Congress Avenue, BCMM 254b (Lab: BCMM 243/245) New Haven, CT 06519-1418

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Vesicle traffic and organelle inheritance

The goal of our research program is to understand how the specificity of vesicle traffic is maintained and how organelles are inherited from mother to daughter cells.

Vesicle Traffic
For our studies on vesicle traffic, we have focused on the multiprotein complex called TRAPP. There are two forms of the TRAPP complex, TRAPP I and TRAPP II. TRAPP I is required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi, while TRAPP II is required for traffic from the early endosome to the Golgi and within the Golgi. Interestingly, spondyloepiphyseal dysplasia tardia, a recessive disorder in bone formation is caused by mutations in the human orthologue of a TRAPP subunit.

Using a vesicle binding assay that employs in vitro formed ER-derived vesicles and pure TRAPP I, we have demonstrated that TRAPP I specifically binds to ER to Golgi vesicles. These findings imply that TRAPP I plays a key role in conferring the specificity of ER to Golgi vesicle traffic. TRAPP I binds to coated ER-derived vesicle via an interaction with the coat cargo adapter complex (see Figure), linking TRAPP I dependent vesicle binding to cargo recognition. Once binding occurs, TRAPP I activates the small GTPase Ypt1p, converting it from its GDP-bound to its GTP-bound form. The activation of Ypt1p by TRAPP I may be the signal that the vesicle has reached its correct acceptor compartment. This then leads to the recruitment of other components, such as Uso1p. The pairing of the SNAREs, a class of membrane proteins that are required for membrane fusion, is the final step in docking an ER-derived vesicle to the Golgi.

Organelle Inheritance
It is the goal of these studies to define the process by which the ER is delivered into daughter cells. To achieve this goal a genetic approach has been used to identify the machinery that moves ER tubules from mother to daughter cells. This approach has led to the identification of a collection of genes whose products are required for ER inheritance. A track and motor that moves ER tubules into daughter cells, as well as a putative receptor for cortical ER in daughter cells have been identified. Orthologues of these components are present in higher cells.

 

A model for the role of TRAPP I in tethering ER to Golgi vesicles. Cargo, which buds from the ER, is packaged into coated vesicles (1). TRAPP I then binds to the coat cargo adaptor complex on the vesicle to tether it to the cis-Golgi (2). Following TRAPP I-dependent activation of Ypt1p (blue; 3), possible effectors such as Uso1p are recruited to aid in vesicle tethering (4).

Selected Publications

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.

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.
(Commentaries on this paper  appeared  in Dev Cell and Curr Biol)

Du, Y., Walker, L., Novick, P. and Ferro-Novick, S. 2006. Ptc1p regulates  cortical  ER inheritance  via  Slt2p. EMBO J. 25: 4413-4422.
(This paper was highlighted in  EMBO J)

Yu, S., Satoh, A., Pypaert, M., Muller, K., Hay,  J.C. and Ferro-Novick, S. 2006. mBet3p is required  for homotypic  COPII vesicle tethering  in mammalian cells.   J. Cell Biol. 174:359-368.

DeCreane, J.O., Coleman,  J., Estrada de Martin, P., Pypaert,M., Anderson, S., Yates III, J.R., Ferro-Novick, S and Novick, P. 2006. Rtn1p is involved in structuring  the  cortical  ER. Mol. Biol. Cell 17:3009-3020.

Cai, H., Zhang, Y., Pypaert, M., Walker, L. and Ferro-Novick, S. 2005. Trs120p mediates  traffic from the early endosome to a late Golgi compartment.  J. Cell Biol. 171:823-833.

Estrada de Martin,P., Novick,P. and Ferro-Novick,S.  2005. The organization,  structure and inheritance of the ER in higher and lower  eukaryotes.  Biochem. Cell  Biol. 83:752-761.