Ronald Wek
Indiana University School of Medicine
Nutrition, Obesity and Diabetes
Nutrition and translational control
We address the impact of essential amino acid (EAA) nutrition on human health. While increased dietary protein helps maintain muscle mass and function, there are emerging reports associating dietary restriction of EAAs with leanness, longevity and reduced incidence of chronic disease. Recent research also suggests that while amino acid insufficiency can reduce growth, it can also act to increase resistance to surgical stress, improve metabolic fitness and slow metabolic aging. This uncoupling between growth and health raises important questions concerning the relationship between EAA nutrition and homeostatic control of proteins. Our research is focused on cellular sensing of amino acid insufficiency through the GCN2 protein kinase, which activates the Integrated Stress Response (ISR). The ISR reprograms translational control for optimal tissue management of dietary restriction of EAAs. Using cell culture and animal model systems of EAA imbalances, we seek to understand how EAA impacts protein homeostasis, with the goal of better prevention and treatment of chronic diseases such as obesity, metabolic syndrome and age-related sarcopenia. This research is carried out in collaboration with Dr. Tracy Anthony (Rutgers University).
Diabetes, the Stress Response and UPR
A major research focus is the unfolded protein response (UPR), a stress response pathway involving both transcriptional and translation regulatory mechanisms that are activated by endoplasmic reticulum (ER) stress. Proteins targeted for the secretory pathway are translocated into the lumen of the endoplasmic reticulum (ER), upon which the proteins are folded and processed prior to being transported to the Golgi apparatus for eventual protein secretion. In the case of professional secretory cells such as the beta cells of islets that release insulin, there is a high protein load entering the ER that can cause accumulation of unfolded proteins. The resulting activation of the UPR induces gene expression programs that enhance the processing capacity of the ER. However if activation of the UPR is prolonged or inappropriate, the UPR can instead become maladaptive and contribute to loss of beta cells and the pathologies of obesity and diabetes. Our research focuses on the roles that the UPR plays in adapting to disruptions in protein homeostasis, with an eye towards better prevention, diagnosis, and treatment of diabetes and related metabolic diseases.
References:
Teske, B.F., Fusakio, M.E., Zhou, D., Shan, J., McClintick, J.N., Kilberg, M.S., and Wek, R.C. (2013) CHOP Induces Activating Transcription Factor 5 (ATF5) to Trigger Apoptosis in Response to Perturbations in Protein Homeostasis. Molecular Biology of the Cell 24, 2477- 2490.
Teske, B.F., Wek, S.A., Bunpo, P., Cundiff, J.K., McClintick, J.N., Anthony, T.G., and Wek, R.C. (2011) The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Molecular Biology of the Cell 22, 4390-4405.
Wek, R.C., and Staschke, K.A. (2010) How do tumours adapt to nutrient stress? EMBO Journal 29, 1946-1947.
Wek, R.C., and Anthony, T.G. (2010) Obesity: stressing about unfolded proteins. Nature Medicine 16, 374-376.
Wek, R.C., and Anthony, T.G. (2009) Beta testing the antioxidant function of eIF2α phosphorylation in diabetes prevention. Cell Metabolism, 10, 1-2.
Bunpo P., Dudley, A., Cundiff J.K., Cavener, D.R., Wek, R.C., Anthony, T.G. (2009) The GCN2 protein kinase is required to activate amino acid deprivation responses in mice treated with the anti-cancer agent, L-asparaginase. Journal of Biological Chemistry 284, 32742-32749.
Wek, R.C., Jiang, H.Y., and Anthony, T.G. (2006) Coping with stress: eIF2 kinases and translational control. Biochemical Society Transactions 34, 7-11. Cited by over 700 manuscripts.
Anthony, T.G., McDaniel, B.J., Byerley, R.L., McGrath, B.C., Cavener, D.R., McNurlan, M.A., and Wek, R.C. (2004) Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. Journal of Biological Chemistry, 279 36553-36561.
Senée, V., Vattem, K.M., Delépine, M., Rainbow, L., Haton, C., Lecoq, A., Shaw, N., Robert, J.- J., Rooman, R., Diatloff-Zito, C., Michaud, J.L., Bin-Abbas, B., Taha, D., Zabel, B., Franceschini, P., Topaloglu, A.K., Lathrop, M., Barrett, T., Nicolino, M., Wek, R.C., Julier, C. (2004) Wolcott-Rallison syndrome: clinical, genetic, and functional study of EIF2AK3 mutations, and suggestion of genetic heterogeneity. Diabetes, 53, 1876-1883.