Elucidation of the UPR in pathogenesis of human diseases

We came across ER stress through our study on pancreatic β cell dysfunction. We discovered that nitric oxide induced ER stress and pancreatic β cells was vulnerable to ER stress, proposing ER stress as a novel pathogenesis of diabetes [1]. Subsequently, we demonstrated that diabetes was occurred solely by ER stress through the analysis of Akita diabetes mice [2]. Furthermore, we identified novel unfolded protein response (UPR) so-called cotranslocational ER protein degradation, which protected mice from ER stress-mediated diabetes [3]. To delve deeper into the role of UPR in both physiological and pathological conditions, we have utilized tissue-specific knockout of UPR-regulating factors in addition to systemic knockout in mice. Through the analysis of pancreatic β cell-specific ATF4 knockout mice, we showed that ATF4 is essential for essential for glucose-stimulated insulin secretion under physiological conditions [4] and for maintaining βcell identity under diabetic conditions [5]. Through collaborative research, it has been discovered that the UPR plays important roles in neuronal protection [6], control of thermogenesis [7], regulation of innate immune response [8], cause of insulin resistance [9], and formation of atherosclerosis [10]. Thus, the UPR is not limited to the quality control of proteins in the endoplasmic reticulum (ER) but is also involved in regulating various cellular functions and is a contributing factor in several diseases. Our goal is to gain a comprehensive understanding of ER stress response through future research.

　　　　　　　　1.   Proc Natl Acad Sci USA 98, 10845-10850 (2001)

　　　　　　　　2.   J Clin Invest 109, 525-532 (2002)

　　　　　　　　3.   Cell 126, 727-739 (2006)

　　　　　　　　4.   Biochem Biophys Res Commun 611, 165-171 (2022)

　　　　　　　　5.   Mol Metab 54, 101338 (2021)

　　　　　　　　6.    Sci Rep 11, 13086 (2021)

　　　　　　　　7.    Life Sci Alliance 3 (2020)

　　　　　　　　8.    Cell 177, 1201-1216 e1219 (2019)

　　　　　　　　9.    Cell Rep 18, 2045-2057 (2017)

　　　　　　　　10.   Circulation 124, 830-839 (2011)

Drug discovery research targeting ER stress

Accumulated evidence show that ER stress is a causative factor in the onset and exacerbation of various diseases. These disease mechanisms can be broadly classified into three categories. The first is diseases such as diabetes, in which improperly folded proteins accumulate in the ER and have harmful effects on cells. The second is a disease in which the UPR is reduced, rendering cells vulnerable to diseases such as neurodegenerative diseases and viral infections. The third is a disease, such as cancer, in which cells proliferate even in harsh tumor microenvironments by ecracking the UPR. To overcome these diseases, drug development strategies must be tailored to the specific underlying pathologies. For the first category of diseases, chemical chaperones that assist protein folding can be used, while for the second category, UPR activators that enhance ER function can be employed. For the third category, UPR inhibitors that prevent the misuse of UPR. We have established the cell-based high throughput screening system based on the UPR pathway. Using this system, we have identified IBT21 [11] and KM04794 [12] through a screening of hundreds of thousands of compounds. IBT21 has stronger chemical chaperone activity than 4PBA and TUDCA [11], which were approved by the FDA as ALS therapeutics in 2022. Therefore, IBT21 is expected as a potenti drug candidate for various ER stress-related diseases, including neurodegenerative diseases. Additionally, KM04794 regulates proteostasis in the ER and enhances insulin synthesis in pancreatic β cells, leading to improved insulin secretion [12]. In our collaborative research, we were able to rediscover the function of compounds known for their anti-diabetic effects, revealing their role in regulating endoplasmic reticulum (ER) stress and the ER stress response [13] [14].　Our approach to drug discovery based on the molecular mechanisms of the UPR has yielded promising results, and we plan to continue screening for more potent compounds from various compound libraries.

　　　　　　　　　　11.  Elife 8 (2019)

　　　　　　　　　　12.  Cell Chem Biol 29, 996-1009 (2022)

　　　　　　　　　　13.  Diabetes 61, 3084-3093 (2012)

　　　　　　　　　　14 . Diabetes 71, 424-439 (2022)