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Carlos B. Hirschberg Professor and Chair 715 Albany Street, Evans, room 437, Boston, MA 02118-2394 617/414-1040 (tel.) 617/414-1041 (fax) chirschb@bu.edu

education

Ph.D. University of Illinois, Urbana, 1970
Postdoctoral Training: Harvard University, 1970-1972; Massachusetts Institute of Technology, 1972-1974

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 transport 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.


representative publications

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. (2006) Nucleotide Sugar Transporters of the Golgi Apparatus: From Basic Sciences to Diseases. Accounts of Chemical Research. 39, 805-812.

Bredeston, L., Caffaro, C., Samuelson, J. and Hirschberg, C.B. (2005) Golgi and endoplasmic reticulum functions take place in different subcellular compartments of Entamoeba histolytica. J. Biol. Chem. 280, 32168-32176.

Uccelletti, D., O'Callaghan, C., Berninsone, P., Zemtseva, I., Abeijon, C., and Hirschberg, C.B. (2004) ire- 1-dependent Transcriptional Up-regulation of a Lumenal Uridine Diphosphatase from Caenorhabditis elegans. J. Biol. Chem. 279:27390-27398.

Cipollo, J.F., Awad, A., Costello, C.E., Robbins, P.W. and Hirschberg, C.B. (2004) Biosynthesis in vitro of Caenorhabditis elegans phosphorylcholine oligosaccharides. Proc. Natl. Acad. Sci. USA 101: 3404-3408. 

Hirschberg CB (2001). Golgi apparatus nucleotide sugar transport and Leukocyte Adhesion Deficiency II. Journal of Clinical Investigation 108:3-6.

Berninsone P, Hwang HY, Zemtseva I, Horvitz, H.R.  and Hirschberg CB (2001). SQV-7, a protein involved in Caenorhabditis elegans epithelial invagination and early embryogenesis, transports UDP-glucuronic acid, UDP-N- acetylgalactosamine, and UDP-galactose. Proc Natl Acad Sci USA 98:3738-43.