Randal J. Kaufman, Ph.D.
Randal J. Kaufman's Research Focus
The Kaufman lab is focused on understanding the fundamental mechanisms that regulate protein folding and the cellular responses to the accumulation of unfolded/misfolded proteins within the Endoplasmic Reticulum (ER). When proteins fail to fold correctly, they don’t work properly. More importantly, misfolded proteins accumulate with age and cause cellular toxicity, leading to almost every disease associated with aging. In many degenerative diseases, including neurological, metabolic, genetic, and inflammatory diseases, it’s thought that the accumulation of misfolded proteins leads to cellular dysfunction and death.
Dr. Kaufman’s research has focused for more than 30 years on mechanisms that regulate proper protein folding in the ER; this work contributed to the discovery of the UPR in the mid 1980s. The UPR pathways, mediated by PERK, IRE1, and ATF6, coordinate primarily an adaptive response. More recently, his research has focused on molecular mechanisms that establish the apoptotic program in response to protein misfolding in the ER, studies that have shed light on the mechanism by which cancer cells survive in a stressful environment.
Randal J. Kaufman's Research Report
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 (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/misfolded proteins within the ER induces an adaptive stress response known as the Unfolded Protein Response (UPR). The UPR signal is transduced from the ER lumen to cytoplasm and nucleus by three transmembrane proteins IRE1, ATF6, and PERK. UPR activation induces the expression 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. In addition, 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 attenuates translation of most cellular mRNAs but selectively induces translation of the transcription factor ATF4. We 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, mRNA 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 Parkinson's disease and Alzheimer's disease.
Randal J. Kaufman's Bio
Dr. Randal Kaufman previously served as professor of Biological Chemistry and Internal Medicine and Howard Hughes Medical Research Institute investigator at the University of Michigan Medical School. He received his Ph.D. in pharmacology from Stanford University, where he studied gene amplification as a mechanism by which cells become resistant to anticancer agents. He was a Helen Hay Whitney fellow with Nobel Laureate Dr. Phillip Sharp at the Center for Cancer Research at the Massachusetts Institute of Technology (M.I.T.), where he developed gene transfer technologies based on gene amplification and expression in mammalian cells. He did his postdoctoral work at the Center for Cancer Research at M.I.T. In the 1980s, Dr. Kaufman’s experience with gene transfer and engineering led him to become a founding scientist at Genetics Institute Inc., where he engineered mammalian cells for high-level expression of therapeutic proteins, such as clotting factors that are now used to treat individuals with hemophilia. Dr. Kaufman joined Sanford Burnham Prebys in 2011.
Postdoctoral, Center for Cancer Research, M.I.T.
Ph.D., Stanford University
B.A., University of Colorado
7/2011 - Present Adjunct Professor, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI
Honors and Recognition
2006: AAAS Fellow
2000: Distinguished Investigator Award-MI Hemophilia Society
1999: Investigator Recognition Award, International Society of Thrombosis and Haemostasis
1998: International Association Francaise Des Hemophiles Award
1993: Dr. Murray Thelin Award
Chop/Ddit3 depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice.
Yong J, Parekh VS, Reilly SM, Nayak J, Chen Z, Lebeaupin C, Jang I, Zhang J, Prakash TP, Sun H, Murray S, Guo S, Ayala JE, Satin LS, Saltiel AR, Kaufman RJ
Sci Transl Med 2021 Jul 28 ;13(604)
Mechanisms, regulation and functions of the unfolded protein response.
Hetz C, Zhang K, Kaufman RJ
Nat Rev Mol Cell Biol 2020 Aug ;21(8):421-438
Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.
Yong J, Johnson JD, Arvan P, Han J, Kaufman RJ
Nat Rev Endocrinol 2021 Aug ;17(8):455-467
Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress.
Hung HH, Nagatsuka Y, Soldà T, Kodali VK, Iwabuchi K, Kamiguchi H, Kano K, Matsuo I, Ikeda K, Kaufman RJ, Molinari M, Greimel P, Hirabayashi Y
Proc Natl Acad Sci U S A 2022 Dec 20 ;119(51):e2214957119
Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets.
Tran DT, Pottekat A, Lee K, Raghunathan M, Loguercio S, Mir SA, Paton AW, Paton JC, Arvan P, Kaufman RJ, Itkin-Ansari P
J Clin Endocrinol Metab 2022 Nov 23 ;107(11):3100-3110
ER stress and inflammation crosstalk in obesity.
Ajoolabady A, Lebeaupin C, Wu NN, Kaufman RJ, Ren J
Med Res Rev 2023 Jan ;43(1):5-30
IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice.
Butterfield JSS, Yamada K, Bertolini TB, Syed F, Kumar SRP, Li X, Arisa S, Piñeros AR, Tapia A, Rogers CA, Li N, Rana J, Biswas M, Terhorst C, Kaufman RJ, de Jong YP, Herzog RW
Mol Ther 2022 Dec 7 ;30(12):3552-3569
Endoplasmic reticulum stress in liver diseases.
Ajoolabady A, Kaplowitz N, Lebeaupin C, Kroemer G, Kaufman RJ, Malhi H, Ren J
Hepatology 2023 Feb 1 ;77(2):619-639
In Vitro Stimulation of IRE1α/XBP1-Deficient B Cells with LPS.
Zhu H, Jiang C, Kaufman RJ, Li H, Singh N
Methods Mol Biol 2022 ;2378:221-231