National Institute of Infectious Diseases
Lipid transport via interorganelle communication zones of the endoplasmic reticulum
In eukaryotic cells, various types of lipids are synthesized in the endoplasmic reticulum (ER) and are then delivered from the ER to other organelles. The ceramide transport protein CERT mediates the transfer of ceramide from the ER to the Golgi apparatus for the synthesis of sphingomyelin in mammalian cells. Since CERT was discovered as the molecular machinery for the interorganelle trafficking of ceramide at ER-Golgi membrane contact sites (MCSs), a number of lipid-transfer proteins have been found to play key roles in the interorganelle transport of diverse lipid types in many organisms. Nevertheless, the mechanisms by which organelle MCSs, a type of organelle zone, are formed, and how the formation and function of MCSs are regulated remain poorly understood. There are several main purposes in this research project. We aim to identify genes, the products of which are involved in the formation of ER-Golgi MCSs, by genome-wide screening. We also aim to elucidate the mechanisms underlying the functional regulation of CERT. Furthermore, in collaboration with the co-investigators Mie SHIMOJIMA (who has studied the interplay between the ER and chloroplasts in lipid metabolism in plants) and Kaoru KATO (who is an expert on super-resolution microscopy), we aim to find a common principle in inter-organelle communication at MCSs from the aspect of the metabolism and trafficking of lipids.
- Yamaji, T., Hanamatsu, H., Sekizuka, T., Kuroda, M., Ohnishi, M., Furukawa, J., Yahiro, K., and Hanada, K. (2019) A CRISPR screen using subtilase cytotoxin identifies SLC39A9 as a glycan-regulating factor, iScience, 15, 407-420. doi: 10.1016/j.isci.2019.05.005
- Yamaji, T., Sekizuka, T., Kuroda, M., and Hanada, K. (2019) A CRISPR screen identifies LAPTM4A and TM9SF proteins as glycolipid-regulating factors, iScience, 11, 409-424. | DOI:org/10.1016/j.isci.2018.12.039.
- Nakao, N., Ueno, M., Sakai, S., Egawa, D., Hanzawa, H., Kawasaki, S., Kumagai, K., Suzuki, M., Kobayashi, S., and Hanada, K. (2019) Natural ligand-nonmimetic inhibitors to the lipid transfer protein CERT, Comms. Chem. 2, Article no 20. doi: 10.1038/s42004-019-0118-3 (N.N., M.U., and S.S. are co-first authors. S.K. and K.H. are co-correspondence)
- Sugiki, T., Egawa, D., Kumagai, K., Kojima, C., Fujiwara, T., Takeuchi, K., Shimada, I., Hanada, K., and Takahashi, H. (2018) Phosphoinositide binding by the PH domain in ceramide transfer protein (CERT) is inhibited by hyperphosphorylation of an adjacent serine-repeat motif. J. Biol. Chem., 293(28), 11206-11217. (T.S. and D.E. are co-first authors. K.H. and H.T. are co-correspondence)
- Otsuki, N., Sakata, M., Saito, K., Okamoto, K., Mori, Y., Hanada, K., Takeda, M. (2018) Both sphingomyelin and cholesterol in the host cell membrane are essential for Rubella virus J. Virol., 92, e01130-17. (K.H. and M.T. are co-correspondence. This article was selected as Spotlight of the issue)
- Yamaji, T., Horie, A., Tachida, Y., Sakuma, C., Suzuki, Y., Kushi, Y., and Hanada, K. (2016) Role of intracellular lipid logistics in the preferential usage of very long chain-ceramides in glucosylceramide. Int. J. Mol. Sci. 17, 1761
- Kumagai, K., Kawano-Kawada, M., and Hanada, K. (2014) Phosphoregulation of the ceramide transport protein CERT at serine 315 in the interaction with VAMP-associated protein (VAP) for inter-organelle trafficking of ceramide in mammalian cells. J. Biol. Chem. 289, 10748-10760
- Yamaji, T., and Hanada, K. (2014) Establishment of HeLa cell mutants deficient in sphingolipid-related genes by using TALENs. PLoS One 9, e88124
- Sugiki, T., Takeuchi, K., Yamaji, T., Takano, T., Tokunaga, Y., Kumagai, K., Hanada, K., Takahashi, H., and Shimada, I. (2012) Structural basis for the Golgi-association by the pleckstrin homology domain of the ceramide trafficking protein CERT. J. Biol. Chem. 287, 33706-33718
- Yamaji, T., Nishikawa, K., and Hanada, K. (2010) Transmembrane BAX inhibitor motif containing (TMBIM) family proteins perturb a trans-Golgi network enzyme, Gb3 synthase, and reduces Gb3 biosynthesis. J. Biol. Chem. 285, 35505-35518
- Tomishige, N., Kumagai, K., Kusuda, J., Nishijima, M., and Hanada, K. (2009) Casein kinase Igamma2 down-regulates trafficking of ceramide in the synthesis of sphingomyelin. Mol. Biol. Cell 20, 348-357
- Kudo, N., Kumagai, K., Tomishige, N., Yamaji, T., Wakatsuki, S., Nishijima, M., Hanada, K., and Kato, R. (2008) Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. Natl. Acad. Sci. U.S.A. 105, 488-493
- Kumagai, K., Kawano, M., Shinkai-Ouchi, F., Nishijima, M., and Hanada, K. (2007) Inter-organelle trafficking of ceramide is regulated by phosphorylation-dependent co-operativity between the PH and START domains of CERT. J. Biol. Chem. 282, 17758-17766
- Kawano, M., Kumagai, K., Nishijima, M., and Hanada, K. (2006) Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT. J. Biol. Chem. 281, 30279-30288
- Hanada, K., Kumagai, K., Yasuda, S., Miura, Y., Kawano, M., Fukasawa, M., and Nishijima, M. (2003) Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803-809
- Kumagai, K., and Hanada, K. (2019) Structure, functions, and regulation of CERT, a lipid-transfer protein for the delivery of ceramide at the ER-Golgi membrane contact sites (invited review), FEBS Let, in press. (K.K. and K.H. are co-correspondence) doi:10.1002/1873-3468.13511
- Hanada, K. (2018) Lipid transfer proteins rectify inter-organelle flux and accurately deliver lipids at membrane contact sites (Invited review). J. Lipid Res., 59(8), 1341-1366.
- Yamaji, T., and Hanada, K. (2015) Sphingolipid metabolism and interorganellar transport: localization of sphingolipid enzymes and lipid transfer proteins. Traffic 16, 101-122
- Hanada, K. (2014) Co-evolution of sphingomyelin and the ceramide transport protein CERT, Biochim. Biophys. Acta, 1841, 704-719, 2014 [Corrigendum (2014) 1841, 1561-1562]
- Hanada, K. (2006) Discovery of the molecular machinery CERT for endoplasmic reticulum-to-Golgi trafficking of ceramide. Mol. Cell. Biochem. 286, 23-31.