Carlos Hirschberg

Research Description

The Role of Novel Regulation of Posttranslational Modifications in Development and Disease

Our laboratory is interested in studying the biogenesis, structure, and function of lower and higher eukaryotes’ cell surfaces and the extracellular matrix by using a combined biochemical, molecular biological, and genetic approach. Our particular effort is focused on glycoproteins, glycolipids, and glycosaminoglycans. These play important roles in the regulation of cell growth, intercellular recognition, cell adhesion, and as receptors for hormones, toxins, and growth factors.

A major research effort has centered around mechanisms of glycosylation, sulfation, and phosphorylation of the above-named compounds. Specific questions which are being asked include the intracellular membrane topography of glycosylation, sulfation, and phosphorylation reactions and how precursors are transported from their intracellular site of synthesis to the site(s) of glycosylation, sulfation, and phosphorylation. We have characterized a number of transporters in the membrane of the rough endoplasmic reticulum and Golgi apparatus which transports precursors into the lumen of these organelles. These transporters are antiporters. We and others have described Chinese hamster ovary cells, yeast, protozoa, nematodes, insects, and plants which are defective in transport of sugar nucleotides into the Golgi apparatus lumen. These mutants have a developmentally impaired phenotype and can cause a virulent wild type organism to become avirulent, demonstrating that the transporters are of physiologic relevance and may become drug targets. Recently the first diseases in such transporters were described: leukocyte adhesion deficiency II syndrome in humans and complex vertebral malformation in bovines. We have purified and cloned some of these transporters by using biochemical and molecular biological approaches, including genetic complementation. More recently, we are also studying the function of these transporters in C. elegans and are cloning and disrupting the genes of enzymes involved in the above posttranslational modifications, i.e., a Golgi GDPase from K. lactis, Candida albicans, and C. elegans. This approach should enable us to determine the functions of specific glycoproteins and glycosaminoglycans during development.

Publications

Caffaro CE, Koshy AA, Liu L, Zeiner GM, Hirschberg CB, Boothroyd JC (2013). A nucleotide sugar transporter involved in glycosylation of the Toxoplasma tissue cyst wall is required for efficient persistence of bradyzoites. PLoS Pathog. 2013;9(5).

Liu L, Xu YX, Caradonna KL, Kruzel EK, Burleigh BA, Bangs JD and Hirschberg CB (2013). Inhibition of nucleotide sugar transport in Trypanosoma brucei alters surface glycosylation. J Biol Chem. 2013 Apr 12;288(15):10599-615.

Liu L, Hirschberg CB. (2013). Developmental diseases caused by impaired nucleotide sugar transporters. Glycoconj J. 2013 Jan;30(1):5-10.

Xu, Y. X., Liu, L., Caffaro, C. E. and Hirschberg, C. B. (2010). Inhibition of Golgi Apparatus glycosylation causes endoplasmic reticulum stress and decreased protein synthesis. J. Biol. Chem. 285:24600–24608.

Liu, L., Xu, Y. X. and Hirschberg, C. B. (2010). The Role of Nucleotide Sugar Transporters in Development. Semin. Cell and Dev. Biol. 21, 600–608.

Uccelletti, D., Pascoli, A., Farina, F., Alberti, A., Mancini, P., Hirschberg, C. B., Palleschi, C. (2008). APY-1, a Novel Caenorhabditis elegans Apyrase involved in UPR Signalling and Stress Responses. Mol. Biol. Cell, 19, 1337–1345.

Caffaro, C. E., Luhn, K., Bakker, H., Vestweber, D., Samuelson, J., Berninsone, P., and Hirschberg, C. B. (2008). A single Caenorhabditis elegans Golgi apparatus-type Transporter of UDP-Glucose, UDP-Galactose, UDP-N-Acetylglucosamine, and UDP-N-Acetylgalactosamine. Biochemistry, 47, 4337–4344.

Caffaro, C. E., Hirschberg, C. B. and Berninsone, P. M. (2007). Functional Redundancy between Two Caenorhabditis elegans Nucleotide Sugar Transporters with a novel transport mechanism. J. Biol. Chem. 282, 27970–27975.

Caffaro, C. E., Hirschberg, C. B. and Berninsone, P. M. (2006). Independent and simultaneous translocation of two substrates by a nucleotide sugar transporter. Proc. Natl. Acad. Sci. USA 103, 16176–16181.

Caffaro, C. and Hirschberg, C. B. (2006). Nucleotide Sugar Transporters of the Golgi Apparatus: From Basic Sciences to Diseases. Accounts of Chemical Research. 39, 805–812.