Mechanisms of Translocation of ER Chaperones to the Cell Surface and Immunomodulatory Roles in Cancer and Autoimmunity.
Frontiers in Oncology
Copyright: © 2015 Wiersma, Michalak, Abdullah, Bremer and Eggleton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Endoplasmic reticulum (ER) chaperones (e.g., calreticulin, heat shock proteins, and isomerases) perform a multitude of functions within the ER. However, many of these chaperones can translocate to the cytosol and eventually the surface of cells, particularly during ER stress induced by e.g., drugs, UV irradiation, and microbial stimuli. Once on the cell surface or in the extracellular space, the ER chaperones can take on immunogenic characteristics, as mostly described in the context of cancer, appearing as damage-associated molecular patterns recognized by the immune system. How ER chaperones relocate to the cell surface and interact with other intracellular proteins appears to influence whether a tumor cell is targeted for cell death. The relocation of ER proteins to the cell surface can be exploited to target cancer cells for elimination by immune mechanism. Here we evaluate the evidence for the different mechanisms of ER protein translocation and binding to the cell surface and how ER protein translocation can act as a signal for cancer cells to undergo killing by immunogenic cell death and other cell death pathways. The release of chaperones can also exacerbate underlying autoimmune conditions, such as rheumatoid arthritis and multiple sclerosis, and the immunomodulatory role of extracellular chaperones as potential cancer immunotherapies requires cautious monitoring, particularly in cancer patients with underlying autoimmune disease.
Cornwall Arthritis Trust
Northcott Devon Medical Foundation
Dutchy Health Charity
HCED Iraq Ph.D. Studentship
Canadian Institutes of Health Research
Dutch Cancer Society
Netherlands Organization for Scientific Research
Open access article originally published in Frontiers in Oncology, 2017, Vol. 5, Article no. 7
Vol. 5, Article no. 7
Place of publication