Calreticulin, a therapeutic target?

ABSTRACT

Introduction: Calreticulin is an endoplasmic reticulum (ER) resident protein critical for maintaining Ca²⁺ homeostasis and glycoprotein folding in the ER. The protein has also been identified on the cell surface of apoptotic and necrotic cells and implicated to play a role in immunogenic cell death and other extracellular functions. The molecular events that promote cell surface association of calreticulin are not clear. Under cell stress conditions (environmental, drug induced, hypoxia), calreticulin may be upregulated as it attempts to regulate cell survival, death or repair. The initial signaling mechanisms involved in these processes may be regulated by the unfolded protein response (UPR) and genome damage response (GDR) pathways.

Area covered: Here, the phenomenon of cell surface calreticulin and its extracellular functions are discussed, with a major emphasis on the process of immunogenic cell death. The evidence of how cell surface calreticulin may act as a damage associated molecular pattern molecule is evaluated, in addition to how these properties of the protein can be exploited for therapeutic vaccine development, cancer treatment and mediating other inflammatory processes. In addition, clarification of calreticulin functions from its intracellular, cell surface, and extracellular locations are provided.

Expert opinion: While the protein folding and immune-stimulatory properties of calreticulin can be exploited to develop therapies, the molecular pathways involved remain to be elucidated. Nevertheless, exploiting the multifaceted properties of calreticulin may in the future provide a means to treat a number of diseases.

KEYWORDS:

• Calreticulin
• endoplasmic reticulum
• immunogenic cell death
• cancer

Article highlights

• CALR can be found on the cell surface where it affects both innate and adaptive immunity.

• There are significant variations with respect to the presence of cell surface CALR, that is cell type/lineage and additional treatment required for cell surface appearance.

• CALR alone or bound to other proteins can promote anticancer immunity and has antiangiogenic effects.

• CALR possesses other therapeutic potentials, for example wound healing and is a biomarker of hematopoietic disorders (exon 9 mutation in the CALR gene).

• CALR can be exploited to enhance antigen therapeutic vaccine development.

This box summarizes key points contained in the article.

Acknowledgements

We thank Leslie Gold (NYU) and members of the Michalak lab for helpful comments and suggestions. We thank Hannah Eggleton for assistance with the preparation of Figure 2. Space constraints have not permitted us to cite all whose work has made a valuable contribution to this field for which we apologize in advance.

Declaration of interest

The authors’ research has been supported by grants over many years from the Medical Research Council UK, Arthritis Research UK, Alberta Innovates-Heath Solutions, Canadian Institutes of Health Research (MOP-15291, MOP-15415, MOP-53050), Heart and Stroke Foundation of Canada, and Dutch Cancer Society. M Michalak is a co-holder of a patent on ‘Methods for treating diabetic wounds’ Patent Cooperation Treaty (PCT) publication US12/547,256 and a patent on ‘Composition and methods for purifying calreticulin’ publication No: US20100145016A1. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.