University of Toronto Biochemistry

	Sergio Grinstein Professor Ph.D. Mexico, 1976
	Hospital for Sick Children, McMaster Building, Room 5006 416-813-5727 sga@sickkids.ca

Biological Membranes and Ion Transport

Research Synopsis

Two major areas are under study in my laboratory. The first one investigates the molecular mechanisms utilized by white blood cells to eliminate infectious organisms. More specifically, we are studying the processes whereby macrophages and neutrophils migrate to sites of infection, ingest microbes and destroy them.

The second area deals with the regulation of ion transport and pH of intracellular compartments. We have devised means of measuring the pH and ionic composition of individual organelles within intact live cells and are currently investigating the identity and properties of the molecules responsible for ionic regulation.

Future Research
We anticipate to make extensive use of molecular biology and single-cell spectroscopy to pursue our studies of innate immunity and of ion transport and pH regulation.

Selected Publications

Booth, J.W., Kim, M.-K., Jankowski, A., Schreiber, A., and Grinstein, S. (2002) Contrasting requirements for ubiquitination during Fc¡RIIA internalization by endocytosis versus phagocytosis. EMBO J. 21 :251-258.

Scott, C.C., Cuellar-Mata, P., Matsuo, T., Davidson, H.W. and Grinstein, S. (2002) Role of 3'-phosphoinositides in the maturation of Salmonella-containing vacuoles within host cells. J. Biol. Chem. 277 :12770-12776.

Terebiznik, M., Vieira, O.V., Marcus, S., Trimble, W.S., Meyer, T., Finlay, B. and Grinstein, S. (2002) Elimination of host cell PI(4,5)P2 by the bacterial phosphatase SopB/SigD promotes membrane fission during invasion by Salmonella . Nature Cell Biology 10 :766-773 .

Coppolino, M.G., Dierckman, R., Loijens, J., Collins, R.F., Pouladi, M., Jongstra-Bilen, J., Schreiber, A.D., Trimble, W.S., Anderson , R. and Grinstein, S. (2002) Inhibition of phosphatidylinositol-4-phosphate 5-kinase Ia impairs localized actin remodelling and suppresses phagocytosis. J. Biol. Chem. 277 :43849-43857.

Tse, S.M.L., Furuya, W., Gold, E., Schreiber, A.D., Sandvig, K., Inman, R.D., and Grinstein, S. (2003) Differential role of actin, clathrin and dynamin in Fcg receptor-mediated endocytosis and phagocytosis. J. Biol. Chem. 278 :3331-3338.

Harrison , R.E., Bucci, C., Vieira, O.V., Schroer, T.A. and Grinstein, S. (2003) Phagosomes fuse with lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol. Cell Biol 18 :6494-6506.

Vieira, O.T., Bucci, C., Harrison, R.E., Trimble, W.S., Lanzetti, L., Gruenberg, J., Schreiber, A.D., Stahl, P.D. and Grinstein, S. (2003) Modulation of Rab5 and Rab7 recruitment to phagosomes by phosphatidylinositol 3-kinase. Mol Cell Biol. 7 : 2501-14.

Touret, N., Furuya, W., Forbes, J., Gros, P. and Grinstein, S. (2003) Dynamic traffic through the recycling compartment couples the metal transporter Nramp2 (DMT1) with the transferrin receptor. J. Biol. Chem. 278 :25548-25557.

Jabado, N., Cuellar-Mata, P., Grinstein, s. and Gros, P. (2003) Iron chelators modulate the fusogenic properties of salmonella containing phagosomes. Proc. Nat. Acad. Sci. 100 :6127-6132.

Scott, C.C., Furuya, W., Trimble, W.S. and Grinstein, S. (2003) Activation of store-operated calcium channels: assessment of the role of SNARE-mediated vesicular transport. J. Biol. Chem. 278 :30534-30539.

Jongstra-Bilen, Harrison , R.E. and Grinstein, S. (2003) Fc¡-receptors induce Mac-1 (CD11b/CD18) mobilization and accumulation in the phagocytic cup for optimal phagocytosis. J. Biol. Chem. 278 :45720-45729.

Hayashi H, Szaszi K, Coady-Osberg N, Furuya W, Bretscher AP, Orlowski J, Grinstein S. (2004) Inhibition and redistribution of NHE3, the apical Na+/H+ exchanger, by Clostridium difficile toxin B. J Gen Physiol. 123 :491-504.

Harrison R.E, Brumell JH, Khandani A, Bucci C, Scott CC, Jiang X, Finlay BB, Grinstein S. (2004) Salmonella impairs RILP recruitment to Rab7 during maturation of invasion vacuoles. Mol Biol Cell. 15 :3146-54.

Vieira O.V, Harrison R.E, Scott C.C, Stenmark H, Alexander D, Liu J, Gruenberg J, Schreiber AD, Grinstein S. (2004) Acquisition of Hrs, an essential component of phagosomal maturation, is impaired by mycobacteria. Mol Cell Biol. 24 :4593-4604.

Touret, N., Paroutis, P. Terebiznik, M., Harrison, R., Trinbetta, S., Pypaert, M., Chow, A., Jiang, A., Shaw, J., Yip, C., Moore, H.-P., van der Wel, Houben, D., Peters, P.J., de Chastellier, C., Mellman, I. and Grinstein, S. (2005) Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell , 123 :157-170.

Yeung, T., Terebiznik, M., Yu, L., Silvius, J., Abidi, W.M., Philips, M., Levine, T., Kapus, A. and Grinstein, S. (2006) Receptor activation alters inner surface potential during phagocytosis. Science 313 :347-351.

Mason, D., Mallo, G.V., Terebiznik, M.R., Payrastre, B., Finlay, B.B., Brumell, J.H. and Grinstein, S. (2007) Alteration of epithelial structure and function associated with PtdIns(4,5)P 2 degradation by a bacterial phosphatase. J. Gen. Physiol. 129 :267-283.

Huynh, K.K., Eskelinen, E-L., Scott, C.C., Malevanets, A., Saftig, P. and Grinstein, S. (2007) LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J. 26 (2): 313-324.

Steinberg, B.E., Touret, N., Vargas-Caballero, M. and Grinstein, S. (2007) In situ measurement of the electrical potential across the phagosomal membrane using FRET. Contribution to the proton-motive force. Proc. Natl. Acad. Sci. USA 104: 9523-8.

Steinberg , B.E. and Grinstein S. (2007) Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Science STKE 379 :11.

Yeung, T. Gilbert, G., Shi, J., Silvius, J., Kapus, A. and Grinstein, S. (2008) Membrane phosphatidylserine regulates surface charge and protein localization. Science 319 :210-213.

Last Modified: 9 February 2009, 09:18 AM

Last Modified: 9 February, 2009 9:18 AM