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The Kaufman Lab
Sanford Burnham Prebys Medical Discovery Institute
Neuroscience and Aging Research Center
Research

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 implications 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 Parkinsons disease and Alzheimers disease.

Protein folding is the most error-prone step in gene expression and contributes to all degenerative diseases including neurodegeneration, metabolic syndrome, inflammation and cancer. Protein misfolding causes protein aggregation that causes cell death. Unfortunately there is a dearth of information regarding how protein aggregation is controlled in the cell. In a report published in Mol. Biol. Cell, Dr. Kaufman’s lab describes how protein solubility in the endoplasmic reticulum requires a unique enzyme UGGT1, a gene that was first isolated by Dr. Kaufman years ago. Now the Kaufman lab has demonstrated that this enzyme controls the aggregation of different mutant forms of the protein a-1-antitrypsin(a1-AT), which is produced in the liver. One mutation in (a1-AT), the Z-allele, is the most common cause of liver failure in children. Kaufman’s studies demonstrate that UGGT1 promotes protein solubility of (a1-AT-Z) and protects cells from death. The findings provide novel insight into potential avenues to treat and/or prevent the most common devastating liver disease in children.

Lab Members
kaufman lab
Randal J. Kaufman, Ph.D.
Professor and Director, Degenerative Diseases Program
Endowed Chair of Cell Biology

Randal is the director and professor of the Degenerative Diseases Program, Neuroscience and Aging Center at Sanford Burnham Prebys Medical Discovery Institute (SBP) and an Adjunct Professor in the Department of Pharmacology at the UC San Diego School of Medicine. Randal received his BA at the University of Colorado and went on to obtain his Ph.D. in Pharmacology at Stanford University. Randal continued his postdoctoral studies at the Center for Cancer Research at M.I.T., where he was a Helen Hay Whitney postdoctoral fellow with Nobel Laureate Phillip Allen Sharp. From 1994-2011, Randal served as Professor of Biological Chemistry and Internal Medicine, Endowed Chair of Medicine and Investigator of Howard Hughes Medical Research Institute at the University of Michigan Medical School. In 2011, Randal joined SBP as a Principal Investigator and has continued to focus on the signaling mechanism of unfolded protein response and its role in the pathogenesis of a wide spectrum of diseases.

Zhouji Chen, Ph.D.
Research Associate Professor

Zhouji received his Ph.D. in Nutritional Biochemistry/Animal Science from Michigan State University, East Lansing, MI in 1994. He obtained his postdoctoral training in Biochemistry/Molecular Endocrinology from the Department of Biochemistry of University of Michigan, Ann Arbor, MI. Prior to joining the Kaufman lab in the Spring of 2015, he was a research faculty member at the Department of Medicine of Washington University-St Louis School of Medicine, where he carried out a large body of research work related to metabolic and genetic regulation of lipid metabolism and mechanisms of the pathogenesis of coronary heart disease and non-alcoholic fatty liver disease. His current work is focused on elucidating roles of the protein disulfide isomerase (PDI) family proteins, especially PDIA1, PDIA4, and PDIA6 in health and disease, which are the common targets of the IRE1a-XBP1 and ATF6 pathways in UPR signaling. His recent work identified novel and fundamental roles of PDIA1 in control of lipid homeostasis and post-translational modification of collagen, the most abundant protein in our body. Future research directions include understanding the role of PDIA1 in the pathogenesis of liver fibrosis, cancer, and neurodegenerative disease as well as its role in skeletal development.

Jing Yong, Ph.D.
Staff Scientist

Jing received his Ph.D. in Molecular and Medical Pharmacology from the University of California, Los Angeles in 2009. In 2011, he joined the Kaufman lab and completed two research projects during his Post-Doctoral research: Project 1: Jing investigated the “mysterious” endoplasmic reticulum ATP supply mechanism and discovered that mitochondria supply ATP to the endoplasmic reticulum through CaATiER mechanism (eLife, 2019). Project 2: Jing established and characterized a pancreatic β-cell specific Chop/Ddit3 genetic knock-out mouse model and further elucidated CHOP’s role in coordinating insulin release from pancreatic islets. His discovery paved the way for developing pharmaceutical approaches targeting Chop as a novel therapy for Type 2 Diabetes.

Ruishu Deng, Ph.D.
Senior PostDoctoral Associate

Ruishu received her Ph.D. in Pathology from Peking University in China in 2011. Ruishu joined the Kaufman lab in 2016 as a Postdoctoral Associate. She is currently studying the role of endoplasmic reticulum stress and unfolded protein response pathways in colon cancer and hepatocyte carcinoma. Prior to joining the Kaufman lab, she worked as a Postdoctoral Fellow at City of Hope National Medical Center studying the mechanism of graft versus host disease in murine models.

Insook Jang, Ph.D.
Postdoctoral Associate

Insook received her Ph.D. in Biomedical Sciences from Yonsei University, Seoul, South Korea in 2015. In June 2016, she joined the Kaufman lab as a Postdoctoral Associate where she has characterized the role of PDIA1 in proinsulin maturation and pancreatic β-cell health under diet induced obesity. Her work has been published in eLife in June 2019, and she is currently investigating the mechanism of proinsulin misfolding in Type 2 Diabetes.

Clementine Druelle-Cedano, M.Sc.
Research Associate II

Clémentine received her M.Sc. degree in Cellular and Molecular Biology in 2015 from Lille 1 University in France. In 2016, she joined the APC Microbiome Institute in Ireland as a Research Assistant in the John F. Cryan lab investigating the Brain-Gut-Microbiome axis. She contributed to several projects focusing on G-Coupled Protein Receptors crosstalk and heterodimerization in vitro and their involvement in modulating behavior. In April 2018, she joined the Kaufman lab as a Research Associate where she is currently investigating the role of the endoplasmic reticulum stress and the unfolded protein responses in the initiation and progression of hepatocellular carcinoma.

Alec Duffey
Lab Coordinator

Departed Staff
Cynthia Lebeaupin, Ph.D., Senior PostDoctoral Fellow
Current Position: Gastrointestinal Drug Discovery, Takeda
LuLin Jiang, Ph.D., Staff Scientist
Current Position: : Senior Scientist, BAI-Altos Labs
Yunqian Peng, Ph.D., Postdoctoral Associate
Current Position: Research Scientist, Williams Lab, UT Southwestern Medical Center
Wei Jiang, Ph.D., Postdoctoral Associate
Current Position: Field Application Scientist III, Seer
Shakib Omari, Ph.D., Staff Scientist
Thanyarat (Kae) Promlek, Ph.D., Visiting Researcher
Juthakorn Poothong, Postdoctoral Associate
Allyssa Rasch, Lab Assistant
Jacqueline Lagunas-Acosta, Research Associate I
Current Position: Research Assistant at Abreos Biosciences
Michelle Lee, Lab Assistant

Cynthia Lebeaupin Farewell Lunch (10/26/2023)

Publications

Audrey Kapelanski-Lamoureux,Zhouji Chen, Zu-Hua Gao, Ruishu Deng, Anthoula Lazaris, Cynthia Lebeaupin, Lisa Giles, Jyoti Malhotra, Jing Yong, Chenhui Zou, Ype P. de Jong, Peter Metrakos, Roland W. Herzog, Randal J. Kaufman, December 7, 2022 Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

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. December 12, 2022. Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress.

Chen, Z., Wang, S., Pottekat, A., Duffey, A., Jang, I., Chang, B.H., Cho, J., Finck, B.N., Davidson, N.O., Kaufman, R.J. 2022. Conditional hepatocyte ablation of PDIA1 uncovers its indispensable roles for 1 both APOB and MTTP folding to support VLDL secretion. Revision to be submitted to Elife.

Arunagiri, A., Alam, M., Haataja, L., Sidarala, V., Samy, P., Sadique, N., Jang, I., Soleimanpour, S.A., Satin, L., Itkin-Ansari, P., Kaufman, R.J., Liu, M., Arvan. P. 2022. Detecting Proinsulin Misfolding in the Endoplasmic Reticulum. Submitted to Diabetes.

Tran, D., Pottekat, A., Lee, K., Raghunathan, M., Loguercio, S., Mir, S., Paton, A.W., Paton, J.C., Arvan, P., Kaufman, R.J., Itkin-Ansari, P. 2022. Inflammatory cytokines rewire the proinsulin interaction network in human islets bioRxiv 2022.04.07.487532; doi: https://doi.org/10.1101/2022.04.07.487532. Submitted to Diabetes.

Butterfield, J.S.S., Yamada, K., Bertolini, T.B., Syed, F., Kumar, S.R.P., Li, X., Arisa, S., Piñeros, A.R., Tapia, A., Rogers, C.A., Li, N., Rana, J., Biswas, M., Terhorst, C., Kaufman, R.J., de Jong, Y-P., Herzog, R.W. 2022. IL-15 Blockade Ameliorates Multifactorial Loss of Factor VIII Protein Production by AAV-Transduced Hepatocytes in Hemophilia A Mice. Molecular Therapy (In Press).

Peng, Y., Chen, Z., Jang, I., Arvan, P., Kaufman, R.J. 2020/bioRxiv 2020.01.01.892539; Epitope-tagging of the endogenous murine BiP/GRP78/Hspa5 locus allows direct analysis of the BiP interactome and protein misfolding in vivo. doi: https://doi.org/10.1101/2020.01.01.892539

Complete list of Kaufman Lab publications

Contact

The Kaufman Lab is located at:

Sanford Burnham Prebys Medical Discovery Institute
10901 North Torrey Pines Road
La Jolla, CA 92037

Please direct all lab-related inquiries to Alec Duffey

Please direct all research administrative inquiries to Lindsay Bazett