The ins and outs of calreticulin: from the ER lumen to the extracellular space

Johnson, Steven; Michalak, Marek; Opas, Michał; Eggleton, Paul

doi:10.1016/s0962-8924(01)01926-2

Cited by 308 publications

(238 citation statements)

References 80 publications

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“…A direct link is plausible because accumulation of damaged or unfolded proteins has been known to overwhelm the retention system for chaperones like CALR thereby causing its 'escape' towards the surface. [36][37][38]43 Moreover, this correlation is further supported by the observations that while blocking caspase signaling delays the execution of apoptosis 23 without altering ecto-CALR induction 9 following Hyp-PDT-based phox-ER stress 22 yet, interference with autophagy (via ATG5-silencing) increases accumulation of oxidized proteins, 33 ecto-CALR and cell death, 33 likely by an amplification of ROSmediated ER stress (A. D. Garg and P. Agostinis, unpublished results). Last but not least, we recently found that Hyp-PDT induced an initial reticulophagy in the ER-photodamaged cells, which we revealed by the increase in the colocalization of CALR with the LC3-decorated autophagosomes.…”

Section: Discussionmentioning

confidence: 74%

“…33,34 This is interesting, considering that the surface mobilization of CALR, which is a ROS-dependent process, 9,35 has been linked to the accumulation of damaged proteins. [35][36][37][38] Since autophagy activated by Hyp-PDT counteracts the accumulation of oxidatively damaged proteins, 33 this raises the interesting possibility that autophagy may affect Hyp-PDT-induced ecto-CALR. Moreover, it has been proposed recently that autophagy might be crucial for Hyp-PDT-elicited ATP secretion as well, 16 an avenue that needs further attention.…”

Section: Introductionmentioning

confidence: 99%

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ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

et al. 2013

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Calreticulin surface exposure (ecto-CALR), ATP secretion, maturation of dendritic cells (DCs) and stimulation of T cells are prerequisites for anticancer therapy-induced immunogenic cell death (ICD). Recent evidence suggests that chemotherapy-induced autophagy may positively regulate ICD by favoring ATP secretion. We have recently shown that reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress triggered by hypericin-mediated photodynamic therapy (Hyp-PDT) induces bona fide ICD. However, whether Hyp-PDT-induced autophagy regulates ICD was not explored. Here we showed that, in contrast to expectations, reducing autophagy (by ATG5 knockdown) in cancer cells did not alter ATP secretion after Hyp-PDT. Autophagy-attenuated cancer cells displayed enhanced ecto-CALR induction following Hyp-PDT, which strongly correlated with their inability to clear oxidatively damaged proteins. Furthermore, autophagy-attenuation in Hyp-PDT-treated cancer cells increased their ability to induce DC maturation, IL6 production and proliferation of CD4(+) or CD8(+) T cells, which was accompanied by IFNG production. Thus, our study unravels a role for ROS-induced autophagy in weakening functional interaction between dying cancer cells and the immune system thereby helping in evasion from ICD prerequisites or determinants

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

et al. 2013

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“…The multifunctional calreticulin binds (buffers) Ca 2 þ in the lumen of the ER with high affinity, participates in the folding of newly synthesized glycoproteins, preventing their aggregation, 15 and also performs other cellular functions outside the ER, such as cellular adhesion, and gene expression. 15 Calreticulin is also present on the surface of most cell types, and its level on the surface increases during apoptosis. The precise mechanism initiating externalization of calreticulin to the surface of the plasma membrane is still unclear.…”

Section: Positive Regulators Of Uptake Dying Cellmentioning

confidence: 99%

From regulation of dying cell engulfment to development of anti-cancer therapy

Krysko

Vandenabeele

2007

Cell Death Differ

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Cell death and efficient engulfment of dying cells ensure tissue homeostasis and is involved in pathogenesis. Clearance of dying cells is a complex and dynamic process coordinated by interplay between ligands on dying cell, bridging molecules, and receptors on engulfing cells. In this review, we will discuss recent advances and significance of molecular changes on the surface of dying cells implicated in their recognition and clearance as well as factors released by dying cells that attract macrophages to the site of cell death. It is now becoming apparent that phagocytes use a specific set of mechanisms to discriminate between live and dead cells, and this phenomenon will be illustrated here. Next, we will discuss potential mechanisms by which removal of dying cells could modulate immune responses of phagocytes, in particular of macrophages. Finally, we will address possible strategies for manipulating the immunogenicity of dying cells in experimental cancer therapies.

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“…6,7 When present on the surface of damaged cells, it can serve as an 'eat-me' signal and hence facilitate the recognition and later engulfment of the dying cells by macrophages 8 or by dendritic cells. 5 It is thought that this function determines the immunostimulatory effect of CRT, because presentation of tumor antigens by dendritic cells is indeed required for the immunogenic effect of anthracyclin-treated cancer cells.…”

mentioning

confidence: 99%

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

et al. 2007

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Some chemotherapeutic agents can elicit apoptotic cancer cell death, thereby activating an anticancer immune response that influences therapeutic outcome. We previously reported that anthracyclins are particularly efficient in inducing immunogenic cell death, correlating with the pre-apoptotic exposure of calreticulin (CRT) on the plasma membrane surface of anthracyclintreated tumor cells. Here, we investigated the role of cellular Ca 2 þ homeostasis on CRT exposure. A neuroblastoma cell line (SH-SY5Y) failed to expose CRT in response to anthracyclin treatment. This defect in CRT exposure could be overcome by the overexpression of Reticulon-1C, a manipulation that led to a decrease in the Ca 2 þ concentration within the endoplasmic reticulum lumen. The combination of Reticulon-1C expression and anthracyclin treatment yielded more pronounced endoplasmic reticulum Ca 2 þ depletion than either of the two manipulations alone. Chelation of intracellular (and endoplasmic reticulum) Ca 2 þ , targeted expression of the ligand-binding domain of the IP 3 receptor and inhibition of the sarco-endoplasmic reticulum Ca 2 þ -ATPase pump reduced endoplasmic reticulum Ca 2 þ load and promoted pre-apoptotic CRT exposure on the cell surface, in SH-SY5Y and HeLa cells. These results provide evidence that endoplasmic reticulum Ca 2 þ levels control the exposure of CRT. In contrast to prior belief, apoptotic cell death can be immunogenic and hence elicits an active immune response against dying tumor cells. 1 This is therapeutically relevant because immune defects that compromise the response against apoptotic cells reduce the efficacy of anticancer chemotherapy, both in suitable animal models and in patients. 2 We found that anthracyclins and g-irradiation are particularly efficient in inducing immunogenic cell death, at least in mouse models. [3][4][5] The immunogenicity of cellular demise correlates with the exposure of calreticulin (CRT) on the plasma membrane (PM) surface of stressed tumor cells, a phenomenon that manifests before the cells acquire signs of apoptosis such as phosphatidylserine exposure. Inhibition of CRT exposure curtails the capacity of anthracyclin-treated or irradiated tumor cells to vaccinate against cancer and reduces the therapeutic efficacy of anthracyclins on tumors established in immunocompetent hosts. 3-5 Provision of recombinant CRT or drug-mediated enforcement of CRT exposure rendered per se nonimmunogenic chemotherapies (for instance with etoposide and mitomycin C) immunogenic and boosted their therapeutic efficacy. 5 These results suggest that CRT exposure is both necessary and sufficient to render conventional chemotherapies immunogenic.CRT is an abundant Ca 2 þ -binding chaperone that is mostly present in the endoplasmic reticulum (ER) lumen, although it can also be found in other subcellular localizations. 6,7 When present on the surface of damaged cells, it can serve as an 'eat-me' signal and hence facilitate the recognition and later engulfment of the dying cells by macrophages 8 or by dendrit...

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The ins and outs of calreticulin: from the ER lumen to the extracellular space

Cited by 308 publications

References 80 publications

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

From regulation of dying cell engulfment to development of anti-cancer therapy

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

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