She received a Ph.D. in medical sciences from the Osaka University, Department of Immunoregulation, Research Institute For Microbial Diseases in 1999. She worked as a post-doctoral research fellow at Osaka University, Department of Immunoregulation, Research Institute For Microbial Disieases until 2000, at Department of Biochemistry, Biozentrum of the University of Basel (2000-2002) and at Department of Biochemistry, Sciences II, University of Geneva (2002-2005). In 2005, she became an independent postdoctoral research fellow supported by Programme Marie Heim-Vögtlin fellowship from Swiss National Science Foundation.She became an assistant professor (Swiss National Science Foundation Professorship) in 2007
We are interested in understanding the mechanism and regulation of proteins transport in mammalian cells. All Secretory and transmembrane proteins synthesized in the endoplasmic reticulum (ER) arrive at the Golgi apparatus and then reach their final destinations such as plasma membrane, endosomes, lysosomes. Transport of proteins between these various compartments are mainly mediated by small vesicles which bud from donor compartments and fuse with acceptor compartments. The formation of ER-derived vesicles requires the coat protein complex (COPII) in yeast and mammalian cells. Proteins of different characteristics and structures must exit from the ER to reach their final destination. They can be transmembrane proteins, soluble luminal proteins, diffusible proteins, big bundle-like proteins or lipid-anchored proteins. We would like to address the question whether COPII-vesicles are the only type of vesicles required for ER to Golgi transport of such different cargo proteins. Furthermore, for particular proteins, regulation at the level of ER exit seems critical for its physiological function. How these regulated ER exit is achieved?
In order to study the complexity of ER protein exit, we mainly focus on two classes of proteins.
- Glycosylphosphatidylinositol (GPI)-anchored proteins
GPI-anchored proteins are one class of lipid-anchored proteins found in all eukaryotic cells. We are interested in understanding GPI-anchored proteins transport in mammalian cells with several reasons. GPI-anchored proteins are known to be transported from ER to the Golgi in the separate vesicles from other secretory proteins in yeast. GPI-anchored proteins have been shown to have specific interactions with sphingolipid and sterol within membranes and this interaction might be crucial for their intracellular transport. We are interested in whether GPI-anchored proteins are also incorporated into separate vesicles from other secretory proteins in mammalian cells upon ER exit. In addition, what is the role of lipid interactions for intracellular transport of GPI-anchored proteins in mammalian cells?
- Kv4-family transient potassium channel proteins
Kv4-family transient potassium channel proteins play a critical role for controlling the excitability of neurons and cardiac myocytes. More than 7 proteins are shown to interact with Kv4 and some of them affect subcellular distribution of Kv4 channel protein. Among them, channel interacting proteins KChIPs is the most characterized. Previously, it has been shown that Kv4 requires KChIP1 for its surface expression and uses COPII-independent pathway for ER exit. We would like to know how channel interacting proteins are involved in intracellular transport of Kv4 potassium channel proteins. What is the mechanism for ER exit of Kv4 potassium channel proteins?
She is organizing and teaching practical courses to 3rd year biology students one week per year at University of Geneva.
- Castillon GA, Watanabe R, Taylor M, Schwabe TM, Riezman H. Concentration
of GPI-anchored Proteins upon ER exit in Yeast. Traffic. 2008 (in press )
Watanabe R, Castillon GA, Meury A, Riezman H. The presence of an ER exit
signal determines the protein sorting upon ER exit in yeast.
Biochem J. 2008 Sep 1;414(2):237-45.
Kajiwara K, Watanabe R, Pichler H, Ihara K, Murakami S, Riezman H, Funato K. Yeast ARV1 Is Required for Efficient Delivery of an Early GPI Intermediate to the First Mannosyltransferase during GPI Assembly and Controls Lipid Flow from the Endoplasmic Reticulum. Mol Biol Cell. 2008 May;19(5):2069-82.
Houjou T, Hayakawa J, Watanabe R, Tashima Y, Maeda Y, Kinoshita T, Taguchi R. Changes in molecular species profiles of glycosylphosphatidylinositol anchor precursors in early stages of biosynthesis. J Lipid Res. 2007 Jul;48(7):1599-606.
- Watanabe R, Riezman H: Differential ER exit. Curr Opin Cell Biol 2004 Aug;16(4):350-355
- Sobering AK, Watanabe R, Romeo MJ, Yan BC, Specht CA, Orlean P, Riezman H, Levin DE: Yeast Ras regulates the complex that catalyzes the first step in GPI-anchor biosynthesis at the ER. Cell 2004, 117:637-648
- Watanabe R, Funato K, Venkataraman K, Futerman AH, Riezman H: Sphingolipids are required for the stable membrane association of glycosylphosphatidylinositol-anchored proteins in yeast. J Biol Chem 2002, 277:49538-49544.
- Heese-Peck A, Pichler H, Zanolari B, Watanabe R, Daum G, Riezman H: Multiple functions of sterols in yeast endocytosis. Mol Biol Cell 2002, 13:2664-2680.
- Maeda Y, Watanabe R, Harris CL, Hong Y, Ohishi K, Kinoshita K, Kinoshita T: PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal side of the ER. Embo J 2001, 20:250-261.
- Watanabe R, Murakami Y, Marmor MD, Inoue N, Maeda Y, Hino J, Kangawa K, Julius M, Kinoshita T: Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P and is regulated by DPM2. Embo J 2000, 19:4402-4411.
- Hong Y, Maeda Y, Watanabe R, Inoue N, Ohishi K, Kinoshita T: Requirement of PIG-F and PIG-O for transferring phosphoethanolamine to the third mannose in glycosylphosphatidylinositol. J Biol Chem 2000, 275:20911-20919.
- Watanabe R, Ohishi K, Maeda Y, Nakamura N, Kinoshita T: Mammalian PIG-L and its yeast homologue Gpi12p are N-acetylglucosaminylphosphatidylinositol de-N-acetylases essential in glycosylphosphatidylinositol biosynthesis. Biochem J 1999, 339 ( Pt 1):185-192.
- Hong Y, Ohishi K, Watanabe R, Endo Y, Maeda Y, Kinoshita T: GPI1 stabilizes an enzyme essential in the first step of glycosylphosphatidylinositol biosynthesis. J Biol Chem 1999, 274:18582-18588.
- Hong Y, Maeda Y, Watanabe R, Ohishi K, Mishkind M, Riezman H, Kinoshita T: Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol. J Biol Chem 1999, 274:35099-35106.
- Watanabe R, Inoue N, Westfall B, Taron CH, Orlean P, Takeda J, Kinoshita T: The first step of glycosylphosphatidylinositol biosynthesis is mediated by a complex of PIG-A, PIG-H, PIG-C and GPI1. Embo J 1998, 17:877-885.
- Maeda Y, Tomita S, Watanabe R, Ohishi K, Kinoshita T: DPM2 regulates biosynthesis of dolichol phosphate-mannose in mammalian cells: correct subcellular localization and stabilization of DPM1, and binding of dolichol phosphate. Embo J 1998, 17:4920-4929.
- Nakamura N, Inoue N, Watanabe R, Takahashi M, Takeda J, Stevens VL, Kinoshita T: Expression cloning of PIG-L, a candidate N-acetylglucosaminyl-phosphatidylinositol deacetylase. J Biol Chem 1997, 272:15834-15840.
- Watanabe R, Kinoshita T, Masaki R, Yamamoto A, Takeda J, Inoue N: PIG-A and PIG-H, which participate in glycosylphosphatidylinositol anchor biosynthesis, form a protein complex in the endoplasmic reticulum. J Biol Chem 1996, 271:26868-26875.
- Inoue N, Watanabe R, Takeda J, Kinoshita T: PIG-C, one of the three human genes involved in the first step of glycosylphosphatidylinositol biosynthesis is a homologue of Saccharomyces cerevisiae GPI2. Biochem Biophys Res Commun 1996, 226:193-199.
- Watanabe R, Masui R, Mikawa T, Takamatsu S, Kato R, Kuramitsu S: Interaction of Escherichia coli RecA protein with ATP and its analogues. J Biochem (Tokyo) 1994, 116:960-966.