Can Proteasomes Deliver?
Did you know that proteasomes in beta-cells are emerging as an important area of interest with T1D? These protein complexes play a role in protein degradation in eukaryotic cells, as well as in the regulation of growth, differentiation, gene transcription, signaling and apoptosis3. Made up of either standard or inducible subunits, there are three general types of proteasomes: the s-proteasome (standard), the i-proteasome (i-) and the intermediate proteasome (int-). Research has shown the s-proteasome can improve glucose-stimulated insulin secretion, regulate proinsulin and protect from ER stress3,5. I- and int-proteasomes, however, don’t have such clear functions, especially in the T1D context, where they could be connected to the inflammatory responses. So let’s take a look into some of the recent research:.
The immunoproteasome was studied in INS-1E cells and in human islets, where inflammatory cytokines were observed to upregulate it as a protective response to inflammatory stress5.
- Inhibition of one of the subunits of the proteasome was shown to exacerbate cytokine-induced apoptosis in beta cells, confirming that i-proteasomes regulate apoptosis.
- In response to IFNγ, i-proteasome activity and expression were increased.
The intermediate proteasome was investigated in beta-cells for the first time, revealing that it is constitutively expressed and regulated by inflammatory signals. Low concentrations of IL-1β in INS-1E cells, as well as in mouse and human islets, had an upregulating effect on proteasomal activity3.
UPS: Delivering Ubiquitin to Your Proteins Today
Similar to a busy post office, a complex mesh of enzyme interactions in the ubiquitin-proteasome system (UPS) attaches ubiquitin to a substrate protein that needs to be degraded.The UPS has been an attractive target for pharmaceutical companies, but only a few of the drugs developed have been successful since the multicomplex system of the UPS has many enzymatic reactions and protein rearrangements that are difficult to pinpoint specifically2.
The UPS, along with another process called autophagy, has been shown to regulate important functions in beta-cells – namely protein degradation. Though necessary to regular cell function, these processes may become dysfunctional or overwhelmed with cellular stress in a diabetic context1.
Which is why the UPS could hold the elusive key to alleviating many difficult diseases, including T1D. Interestingly, hyperglycemia can cause changes in proteasome gene expression, and inhibiting the proteasome can increase glucose-induced insulin secretion4. Could even better inhibitors one day allow T1D patients to secrete insulin again?
Main Takeaway? Inflammation has long gone hand in hand with T1D, but it may be time to expand the cellular horizon and investigate how proteasomes and protein-protein interactions could attenuate T1D.
- Hartley, T., Brumell, J., & Volchuk, A. (2009). Emerging roles for the ubiquitin-proteasome system and autophagy in pancreatic β-cells. American Journal of Physiology-Endocrinology and Metabolism, 296(1). doi:10.1152/ajpendo.90538.2008
- Huang, X., Dixit, V. Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res 26, 484–498 (2016). https://doi.org/10.1038/cr.2016.31
- Khilji, M. S., Verstappen, D., Dahlby, T., Burstein Prause, M. C., Pihl, C., Bresson, S. E., Bryde, T. H., Keller Andersen, P. A., Klindt, K., Zivkovic, D., Bousquet-Dubouch, M. P., Tyrberg, B., Mandrup-Poulsen, T., & Marzec, M. T. (2020). The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, low concentrations of interleukin 1 β. PloS one, 15(2), e0222432. https://doi.org/10.1371/journal.pone.0222432
- López-Avalos, M. D., Duvivier-Kali, V., Xu, G., Bonner-Weir, S., Sharma, A., & Weir, G. C. (2006). Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets. Diabetes, 55(5), 1223. doi:10.2337/db05-0450
- Lundh, M., Bugliani, M., Dahlby, T., Chou, D., Wagner, B., Ghiasi, S., De Tata, V., Chen, Z., Lund, M., Davies, M., Marchetti, P., & Mandrup-Poulsen, T. (2017). The immunoproteasome is induced by cytokines and regulates apoptosis in human islets, Journal of Endocrinology, 233(3), 369-379. Retrieved Jul 15, 2020, from https://joe.bioscientifica.com/view/journals/joe/233/3/369.xml