Ronald Wek
Indiana University
School of Medicine
Nutrition, Diabetes, Obesity and the Stress Response
Nutrition, endoplasmic reticulum stress and translational control
We address the impact of amino acids and nutrition on human health. While increased dietary protein helps maintain muscle mass and function, dietary restriction of certain amino acids is associated with longevity and reduced incidence of chronic disease. The uncoupling between growth and health raises important questions concerning the relationship between amino acid 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). Multiple protein kinases phosphorylate eIF2 in the ISR, and eIF2 kinases such as GCN2 can interface with other stress sensing pathways, such as those directed by mTORC1. The ISR reprograms translational control for optimal tissue management of dietary restriction of amino acids. Using cell culture and animal model systems of amino acid imbalances, we seek to understand how these changes impact 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).
eIF2-P triggers global and gene specific translation during ISR
Reciprocal coregulation of GCN2 and mTORC1 during
amino acid insufficiency affects translation and transcriptional expression
The role of the UPR in obesity and diabetes
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, including those in liver.
References:
Misra, J, Carlson KR, Spandau DF, Wek RC (2024)
Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions Nucleic Acid Research 52: 1830-1846
Wek RC, Anthony TG and Staschke KA (2023)
Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response Antioxidant and Redox Signaling 39: 225-409
Misra, J, Holmes MJ, Mirek ET, Langevin M, Kim HG, Carlson KR, Watford M, Dong XC, Anthony, TG and Wek RC (2021)
Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress Nucleic Acid Research 49 : 5726-5742
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.