Abstract
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.
Highlights
The endoplasmic reticulum (ER) is one of many specialized organelles in the cell with diverse and apparently ever expanding functionality
Some of the most plentiful luminal ER chaperones and folding enzymes in order of relative abundance are HSP47, binding immunoglobulin protein (BiP), ERP57, protein disulfide isomerase (PDI), gp96 (GRP94; HSP90), and calreticulin [9], which all fulfill unique functions required for protein assembly
This citrullinated calreticulin preferentially binds to the shared epitope (SE), a sequence motif in the β1 domain of the HLA-DR molecule that is found in 90% of rheumatoid arthritis patients, and potentiates 10,000-fold greater SE-activated signaling in innate immune cells compared to non-citrullinated calreticulin [45, 46]
Summary
The endoplasmic reticulum (ER) is one of many specialized organelles in the cell with diverse and apparently ever expanding functionality. During chemical or physical cell stress, the expression of chaperones are rapidly increased Reasons for this rise in chaperone production are: (a) an attempt to generate correctly folded proteins to help the cell survive or, (b) to assist in shutting down the protein manufacture and aiding degradation in preparation for cell death. Another consequence of this stress response may be the relocation of chaperones to the cell surface via a number of pathways and the eventual release of chaperones into the www.frontiersin.org.
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