Proteostasis is achieved by a cellular network that coordinates protein synthesis, folding and degradation. Aging, transient fluctuations or persistent exposure to environmental or intracellular perturbants of proteostasis can lead to onset of disease, such as neurodegeneration and diabetes. Proteostasis during stress is largely maintained by adaptations in cellular capacity for protein synthesis and folding, thus avoiding the accumulation of damaged proteins that may result in deleterious effects on cell fate. Specifically, the Unfolded Protein Response (UPR) is a stress response that can rapidly change the capacity of the proteostasis network. However, there is a knowledge gap on the stress sensing and adaptation mechanisms during persistent UPR, before development of disease. We propose that the adaptive UPR during persistent stress exposure comprises the coordinated action of transcriptional, translational and metabolic reprogramming that maintains essential cellular functions and stress sensing while preventing cell death caused by ER dysfunction. We propose (i) Characterize a novel mechanism of adaptation to chronic stress using physiologically relevant models of persistent ER stress induction in pancreatic ? cells. (ii) Determine the molecular mechanism of proinsulin mRNA translation in pancreatic ? cells during persistent ER stress and (iii) Characterize a novel adaptive mechanism of increased glucose-stimulated insulin secretion (GSIS) during persistent ER stress in pancreatic ? cells via the upregulation of the nutrient-sensing mitochondrial GTP dependent pathway.
We will study the novel concept that understanding the mechanism of adaptation to chronic endoplasmic reticulum stress before development of disease may lead to therapeutics to delay/prevent disease onset. There is a clear link between diabetes and induction of ER stress in insulin producing ? cells. We will identify the adaptive to ER stress mechanisms in ? cells. These studies will lead to the discovery of biomarkers in progression of diabetes, as well as development of drugs to enhance adaptation and ? cell survival. In addition, the findings should facilitate the design of drugs to fine-tune insulin synthesis in Type 1 and Type 2 diabetes to functional levels that minimize ER stress in ? cells.
|Dery?o, Kamil; Michalec-Wawiórka, Barbara; Krokowski, Dawid et al. (2018) The uL10 protein, a component of the ribosomal P-stalk, is released from the ribosome in nucleolar stress. Biochim Biophys Acta Mol Cell Res 1865:34-47|
|Yadav, Vinita; Gao, Xing-Huang; Willard, Belinda et al. (2017) Hydrogen sulfide modulates eukaryotic translation initiation factor 2? (eIF2?) phosphorylation status in the integrated stress-response pathway. J Biol Chem 292:13143-13153|
|Roy, Debasish; Farabaugh, Kenneth T; Wu, Jing et al. (2017) Coordinated transcriptional control of adipocyte triglyceride lipase (Atgl) by transcription factors Sp1 and peroxisome proliferator-activated receptor ? (PPAR?) during adipocyte differentiation. J Biol Chem 292:14827-14835|
|Krokowski, Dawid; Guan, Bo-Jhih; Wu, Jing et al. (2017) GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells. Cell Rep 21:2895-2910|
|Ziosi, Marcello; Di Meo, Ivano; Kleiner, Giulio et al. (2017) Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway. EMBO Mol Med 9:96-111|
|Guan, Bo-Jhih; van Hoef, Vincent; Jobava, Raul et al. (2017) A Unique ISR Program Determines Cellular Responses to Chronic Stress. Mol Cell 68:885-900.e6|
|Farabaugh, Kenneth T; Majumder, Mithu; Guan, Bo-Jhih et al. (2017) Protein Kinase R Mediates the Inflammatory Response Induced by Hyperosmotic Stress. Mol Cell Biol 37:|
|Kenche, Harshavardhan; Ye, Zhi-Wei; Vedagiri, Kokilavani et al. (2016) Adverse Outcomes Associated with Cigarette Smoke Radicals Related to Damage to Protein-disulfide Isomerase. J Biol Chem 291:4763-78|
|Hu, Juan; Li, Bo; Apisa, Luke et al. (2016) ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23erl/erl mutant mice. Cell Death Dis 7:e2485|
|Hao, Yujun; Samuels, Yardena; Li, Qingling et al. (2016) Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun 7:11971|
Showing the most recent 10 out of 62 publications