Michael Demetriou
Biological Chemistry
Phone: (949) 824-9775
Email: mdemetri@uci.edu
http://www.ucihs.uci.edu/microbio/
Michael Demetriou
Genetic information flows from DNA to macromolecular structures - the dominant force in the molecular organization of life. However, metabolite availability to the Golgi N-glycosylation pathway exerts autonomous control over the assembly of macromolecular complexes on the cell surface, and in this capacity, acts upstream of signaling and gene expression. The structure and multiplicity of N-glycans per protein molecule cooperate to regulate lectin binding and thereby the distribution and function of glycoproteins at the cell surface. Congenital Disorders of Glycosylation provide insight as extreme hypomorphisms while milder defects may encompass many common chronic conditions including autoimmunity, metabolic syndrome and cancer.
Dr. Demetriou’s research is focused on the role of GlcNAc branching on T cell function. GlcNAc branched N-glycans attached to surface glycoproteins bind to galectins, a 15 member family of N-acetylllactosmanine binding lectins, forming a molecular lattice that regulates lateral distribution, clustering, endocytosis and signaling of surface glycoproteins. Galectins bind to surface glycoproteins in proportion to the number of attached N-glycans (i.e. N-X-S/T sites) and the degree of N-glycan GlcNAc-branching, which together determine N-acetyllactosamine content within a glycoprotein. The number of N-X-S/T sites is an encoded feature of protein sequences, while the extent of GlcNAc-branching is conditional to the enzymatic activity and metabolic supply of UDP-GlcNAc to the medial Golgi N-acetylglucosaminyltransferases I, II, IV and V (Mgat1, 2, 4 and 5). Growth promoting r eceptor tyrosine kinases (RTK) tend to have high numbers of N-glycans (e.g. >5), while growth inhibitory CTLA-4, Transforming Growth Factor-β receptor (TβRI and II) and glucose transporters (GLUT2 and GLUT4) have few N-glycans (1, 2, 1 and 1, respectively). The large difference in galectin avidity for high and low multiplicity receptors allows for differential regulation of surface retention and therefore transitions between growth and arrest signaling. Therefore, N-glycan multiplicity and the Golgi-branching pathway impose an order of glycoprotein titration to the cell surface with respect to increasing metabolic flux to GlcNAc branching: first growth factor receptors, then TbR and other low-n glycoproteins. In this manner, N-glycan multiplicity and GlcNAc branching integrates nutrient metabolism to control cellular transitions between cell growth and arrest/differentiation in mammalian cells.
This mechanism has profound implications for autoimmune disease and cancer, two diseases where one or a few cells expand in a pathological manner, apparently beyond normal arrest signaling. Indeed, GlcNAc branching inhibits T cell function and prevents autoimmune disease , but is markedly up-regulated in cancer cells, where it promotes tumor progression and metastasis . Dr. Demetriou’s current research will further define the molecular mechanisms by which metabolism and GlcNAc branching regulate cellular growth versus arrest and determine whether this pathway is disrupted in human autoimmune disease.
Selected Publications:
Demetriou, M., Granovsky, M., Quaggin, S., and Dennis, J. W. (2001). Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409(6821), 733-9.
Chen, I. J., Chen, H. L., and Demetriou, M. (2007). Lateral compartmentalization of T cell receptor versus CD45 by galectin-N-glycan binding and microfilaments coordinate basal and activation signaling. J Biol Chem 282(48), 35361-72.
Grigorian, A., Lee, S. U., Tian, W., Chen, I. J., Gao, G., Mendelsohn, R., Dennis, J. W., and Demetriou, M. (2007). Control of T Cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J Biol Chem 282(27), 20027-35.
Lau, K. S., Partridge, E. A., Grigorian, A., Silvescu, C. I., Reinhold, V. N., Demetriou, M., and Dennis, J. W. (2007). Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129(1), 123-34.
Lee, S. U., Grigorian, A., Pawling, J., Chen, I. J., Gao, G., Mozaffar, T., McKerlie, C., and Demetriou, M. (2007). N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. J Biol Chem 282(46), 33725-34. |
