ER Stress, Human Health and Role of Ca2+-Binding Chaperones
The Endoplasmic Reticulum (ER) is a dynamic and versatile organelle involved in many critical functions of the cell. It is the major Ca2+ storehouse of the cell and the intra luminal [Ca2+] influences several cellular processes including synthesis of protein, lipids and sterols. Therefore, the concentration of Ca2+ is tightly controlled and buffered by several Ca2+-binding proteins in the ER. Several physiological and pathological disturbances can also perturb ER homeostasis, leading to the accumulation of misfolded or unfolded proteins, a condition termed as ER stress. The ER responds well to the stress by activating a series of signaling cascades known as unfolded protein response (UPR) in order to rescue ER functions. The adaptive response of the UPR pathway activates the transcription of several genes including molecular chaperones which aid in the folding of misfolded proteins. In addition to Ca2+-binding (that regulates their function), these ER-resident calcium binding proteins play a major role in folding, post translational processing and quality control of other nascent polypeptide chains and hence can be classified as calcium-binding chaperones (CaBC). The role of CaBC in the UPR pathway is quite indispensable and will be discussed in this chapter.
KeywordsCa2+-Binding proteins Ca2+ Signaling Chaperones Endoplasmic reticulum ER stress Unfolded protein response
The work of the authors presented herein was funded by DST, ICMR, CSIR and DBT. The authors also gratefully thank IIT Madras for the facility and financial support.
- Bourdi, M., Demady, D., Martin, J. L., et al. (1995). cDNA cloning and baculovirus expression of the human liver endoplasmic reticulum P58: Characterization as a protein disulfide isomerase isoform, but not as a protease or a carnitine acyltransferase. Archives of Biochemistry and Biophysics, 323, 397–403.PubMedCrossRefGoogle Scholar
- Lievremont, J. P., Rizzuto, R., Hendershot, L., & Meldolesi, J. (1997). BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. The Journal of Biological Chemistry, 272, 30873–30879.PubMedCrossRefGoogle Scholar
- Logue, S. E., & Gorman, A. M. (2013). Current Concepts in ER Stress-Induced Apoptosis. Journal of Carcinogenesis & Mutagenesis, s6.Google Scholar
- Lucero, H. A., & Kaminer, B. (1999). The role of calcium on the activity of ER calcistorin/protein-disulfide isomerase and the significance of the Cterminal and its calcium binding. A comparison with mammalian protein-disulfide isomerase. The Journal of Biological Chemistry, 274, 3243–3251.PubMedCrossRefGoogle Scholar
- Muchowski, P. J., Schaffar, G., Sittler, A., Wanker, E. E., Hayer-Hartl, M. K., & Hartl, F. U. (2000). Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proceedings of the National Academy of Sciences of the United States of America, 97, 7841–7846.PubMedPubMedCentralCrossRefGoogle Scholar
- Nagashima, Y., Mishiba, K., Suzuki, E., Shimada, Y., Iwata, Y., & Koizumi, N. (2011). Arabidopsis IRE1 catalyses unconventional splicing of bZIP60 mRNA to produce the active transcription factor. Scientific Reports, 1(29). https://doi.org/10.1038/srep00029.
- Nigam, S. K., Goldberg, A. L., Ho, S., Rohde, M. F., Bush, K. T., & Sherman, M. (1994). A set of endoplasmic reticulum proteins possessing properties of molecular chaperones includes Ca(2+)-binding proteins and members of the thioredoxin superfamily. The Journal of Biological Chemistry, 269, 1744–1749.PubMedGoogle Scholar
- Ostrovsky, O., Makarewich, C. A., Snapp, E. L., & Argon, Y. (2009). An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells. Proceedings of the National Academy of Sciences of the United States of America, 106, 11600–11605.PubMedPubMedCentralCrossRefGoogle Scholar
- Song, B., Scheuner, D., Ron, D., Pennathur, S., & Kaufman, R. J. (2008). Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. The Journal of Clinical Investigation, 118, 3378–3389.PubMedPubMedCentralCrossRefGoogle Scholar
- Vekich, J. A., Belmont, P. J., Thuerauf, D. J., & Glembotski, C. C. (2012). Protein disulfide isomerase-associated 6 is an ATF6-inducible ER stress response protein that protects cardiac myocytes from ischemia/reperfusion-mediated cell death. Journal of Molecular and Cellular Cardiology, 53, 259–267.PubMedPubMedCentralCrossRefGoogle Scholar
- Wang, Y., Sun, Y., Fu, Y., et al. (2017). Calumenin relieves cardiac injury by inhibiting ERS-initiated apoptosis during viral myocarditis. International Journal of Clinical and Experimental Pathology, 10, 7277–7284.Google Scholar
- Yoshida, H., Haze, K., Yanagi, H., Yura, T., & Mori, K. (1998). Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. The Journal of Biological Chemistry, 273, 33741–33749.PubMedCrossRefGoogle Scholar