Dr. Brewer has served on the National Science Foundation Graduate Research Fellowship Program as Chair of the Microbiology and Cell Biology Panel. He also serves as an ad hoc reviewer for leading journals, Journal of Cell Biology, Journal of Biological Chemistry, Molecular and Cellular Biology, and Journal of Experimental Medicine.

Research Summary

Endoplasmic reticulum: Studies to delineate the molecular mechanisms that regulate homeostasis of the endoplasmic reticulum (ER) in mammalian cells.

The goal of my research program is to delineate the molecular mechanisms that regulate homeostasis of the endoplasmic reticulum (ER) in mammalian cells. The ER is the gateway to the secretory pathway and serves as a specialized compartment for the maturation of membrane and secreted proteins. As such, the ER is a dynamic organelle that can adapt to accommodate increased demands on the secretory pathway. When the protein folding capacity of the ER is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein folding, maturation, and degradation. In addition, the UPR can lead to cell cycle arrest and, under conditions of chronic ER stress, culminate in apoptosis. We are investigating the role of the UPR in the differentiation of B-lymphocytes into plasma cells that secrete thousands of antibody molecules each second. Antibodies provide host defense against many infectious agents and can mediate autoimmune diseases when produced by autoreactive B-cells, underscoring the need to define the mechanisms underlying plasma cell differentiation and antibody production.

During plasma cell differentiation, the ER expands and adapts to accommodate high-rate antibody production, providing an excellent model in which to investigate the physiologic UPR. Using B-cell culture systems and a combination of molecular, biochemical, and genetic approaches, my laboratory has demonstrated that the UPR mediates events that optimize antibody secretion and orchestrate ER expansion. We intend to further delineate the mechanisms by which the UPR regulates the differentiation and function of plasma cells, thereby gaining a better understanding of the complex relationship between the UPR, ER homeostasis, cellular metabolism, and cell fate.

Recent Publications

Sriburi, R., H. Bommiasamy, G. L. Buldak, G. R. Robbins, M. Frank, S. Jackowski and J. W. Brewer. Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis. 2007. J. Biol. Chem. 282:7024-7034.

Fagone, P., R. Sriburi, C. Ward-Chapman, M. Frank, J. Wang, C. Gunter, J. W. Brewer and S. Jackowski. Phospholipid biosynthesis program underlying membrane expansion during B-lymphocyte differentiation. 2007. J. Biol. Chem. 282:7591-7605.

Gunn, K. E. and J. W. Brewer. Evidence that marginal zone B cells possess an enhanced secretory apparatus and exhibit superior secretory activity. 2006. J. Immunol. 177:3791-3798.

Brewer, J. W. and L. M. Hendershot. Building an antibody factory: a job for the unfolded protein response. 2005. Nat. Immunol. 6: 23-29.

Sriburi, R., S. Jackowski, K. Mori, and J. W. Brewer. XBP1: a link between the unfolded protein response, lipid biosynthesis and biogenesis of the endoplasmic reticulum. 2004. J. Cell Biol. 167: 35-41.

Gunn, K. E., N. M. Gifford, K. Mori, and J. W. Brewer. A role for the unfolded protein response in optimizing antibody secretion. 2004. Mol. Immunol. 41: 919-927.

Gass, J. N., K. E. Gunn, R. Sriburi, and J. W. Brewer. Stressed-out B cells? Plasma cell differentiation and the unfolded protein response. 2004. Trends. Immunol. 25: 17-24.

Gass, J. N., N. M. Gifford, and J. W. Brewer. Activation of an unfolded protein response during differentiation of antibody-secreting B cells. 2002. J. Biol. Chem. 277: 49047-49054.