Professor, Biological Chemistry
Warner-Lambert/Parke-Davis Professor of Medicine
B.A., University of Colorado
Ph.D., Stanford University
Postdoctoral, Center for Cancer Research, M.I.T.
The major portion of our research is aimed at elucidating fundamental mechanisms that regulate protein folding and the cellular responses to the accumulation of unfolded protein within the endoplasmic reticulum (ER). Research into the fundamental processes that regulate protein synthesis and folding within the ER should have impact on the understanding of genetic diseases that result from protein folding defects.
Accumulation of unfolded proteins within the ER induces an adaptive stress response known as the unfolded protein response (UPR). The UPR is transduced from the ER lumen to the nucleus by three transmembrane proteins IRE1, ATF6, and PERK. Activation of the UPR induces the production of a family of basic leucine zipper-containing transcription factors that activate transcription of genes encoding functions to reduce the protein-folding load and increase the protein folding capacity of the ER. IRE1 is a serine/threonine protein kinase and endoribonuclease that signals transcriptional activation by initiating a novel splicing reaction on the mRNA encoding the transcription factor XBP1. UPR activation promotes trafficking of ATF6 from the ER to the Golgi where it is processed to yield a cytosolic fragment that is a potent transcriptional activator. Finally, the protein kinase PERK signals translational attenuation through phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2a) on serine residue 51. This phosphorylation also induces translation of the transcription factor ATF4. We have demonstrated that PERK/eIF2a signaling is essential for glucose-regulated insulin production by pancreatic beta cells, where defects in this pathway result in beta cell dysfunction and diabetes. The findings demonstrate an unprecedented link between glucose metabolism, protein translation, and protein folding and have implication in the treatment of diabetes. Future studies directed to elucidate the molecular logic for the UPR adaptive response will provide fundamental insight into numerous pathological conditions such as viral infection, cancer, inflammation, metabolic disease and atherosclerosis, and protein folding diseases such as Parkinsonâ€™s disease and Alzheimerâ€™s disease.
1993 Dr. Murray Thelin Award
1998 International Association Francaise Des Hemophiles Award â€œPrix Henri Chaigneauâ€
1999 Investigator Recognition Award, International Society of Thrombosis and Haemostasis
2000 Distinguished Investigator Award-MI Hemophilia Society
2006 AAAS Fellow
Zhang, K., Wong, H.N., Song, B., Miller, C.N., Scheuner, D., Kaufman, R.J. (2005) The unfolded protein response sensor IRE1a is required at two distinct steps in B cell lymphopoiesis. J. Clin. Invest. 115(2): 268-281.
Scheuner, D., Mierde, D.V., Song, B., Flamez, D., Creemers, J., Tsukamoto, K., Ribick, M., Schuit, F.C., Kaufman, R.J. (2005) Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nature Med. 11(7):757-764.
Molinari, M., Galli, C., Vanoni, O., Arnold, S.M., Kaufman, R.J. (2005) Persistent glycoprotein misfolding activates the glucosidase II/UGT1-driven calnexin cycle to delay aggregation and loss of folding competence. Mol. Cell 20: 503-512. PMID: 16307915
Shen, X., Sakaki, K., Ellis, R.E., Kaufman, R.J. (2005) Genetic interactions as a consequence of constitutive and Inducible gene regulation mediated by the unfolded protein response in C. elegans. PLOS Genetics 1(3): e37.
Zhang, K., Shen, X., Wu, J., Sakaki, K., Saunders, T., Rutkowski, T.D., Back, S.H, Kaufman, R.J. (2006) Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124(3): 587-599. PMID: 16469704
Zhou, J., Liu, C.Y., Back, S.H., Clark, R.L., Peisach, D., Xu, Z., Kaufman, R.J. (2006). The structure of an unfolded protein response sensor reveals a novel dimerization interface required for IRE1 and PERK activation. Proc. Natl. Acad. Sci. U.S.A. 103(39):14343-14348.
Rutkowski, D.T., Miller, C., Arnold, S.M., Li, J., Wu, J., Gunnison, K., Mori, K., Akha, A.A.S., Raden, D., Kaufman, R.J. (2006) Selective posttranscriptional and posttranslational attenuation of gene expression produces adaptation to ER stress. PLOS Biol. 4(11):e374.
Malhotra, J.D., Miao. H., Zhang, K., Wolfson, A., Pennathur S., Pipe, S.W., Kaufman, R.J. (2008) Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. (In Press). PMID: 19011102
Song, B., Scheuner, D., Ron, D., Pennathur, S., Kaufman, R.J. (2008) Genetic deletion of C/EBP homologous protein CHOP reduces oxidati/ve stress, improves beta cell function and prevents apoptosis. J. Clin. Invest. (In Press).
Sakaki, K., Wu, Kaufman, R.J. (2008) Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum. J. Biol. Chem. 283(22): 15370-80. PMID: 18356160
Wu, J., Rutkowski, D.T.,Dubois, M., Swathirajan, J., Saunders, T., Wang, J., Song, B., Yau, G. D-Y., Kaufman, R.J. (2007) ATF6 alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Developmental Cell 13(3): 351-64.
Rutkowski, D.T., Kang, S-W., Goodman, A.G., Garrison, J.L., Taunton, J., Katze, M.G., Kaufman, R.J.*, Hegde, R. S.* (2007) The role of p58IPK in protecting the stressed endoplasmic reticulum. Mol. Biol. Cell 18(9): 3681-3691. (*Corresponding authors) PMID: 17567950