Calreticulin

Calreticulin (CALR) is a highly conserved chaperone protein found primarily in the endoplasmic reticulum and is involved in a variety of cellular processes, including cell adhesion. It is also involved in protein folding quality control and calcium homeostasis.

Calreticulin and calnexin are able to bind specifically to oligosaccharides containing terminal glucose residues to degrade them. In physiological cell function, truncation of glucose residues from the core oligosaccharide added during N-linked glycosylation is an essential part of protein processing.

In addition to maintaining cellular proteostasis, these cellular CALR functions support Ca2+-dependent processes such as adhesion and integrin signaling and ensure normal antigen presentation on MHC class I molecules (Fucikova J et al. 2021).

Transcription: Calreticulin is also found in the nucleus, suggesting that it may play a role in transcriptional regulation. Calreticulin interacts with the DNA binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element.

Calreticulin may inhibit the binding of the androgen recept or to its hormone-responsive DNA element and inhibit the transcriptional activities of the androgen receptor and retinoic acid recept or in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin may act as an important modulator in the regulation of gene transcription by nuclear hormone receptors.

Calreticulin mutations in essential thrombocythemia and primary myelofibrosis (PMF): Calreticulin mutations have been detected in JAK2-negative/MPL-negative patients with essential thrombocythemia and primary myelofibrosis, making CALR mutations the second most common mutations in myeloproliferative neoplasms. All mutations (insertions or deletions) affected the last exon and resulted in a reading frame shift of the resulting protein. The new protein structure leads to loss of function.

Embryonic heart development: Animal studies have shown that calreticulin in the embryo is essential for heart development.

Other Clinical Significance:

• Calreticulin binds to antibodies of systemic lupus erythematosus and Sjögren's syndrome in which anti-Ro/SSA antibodies were raised. Elevated autoantibody titers to human calreticulin are found in infants with complete congenital heart block.
• Cancer cells that succumb to immunogenic apoptosis express CALR on their surface. This promotes the uptake of these cells by professional phagocytes. CALR mutations impair cellular homeostasis in healthy and pathological tissues, mainly because they interfere with natural and therapy-induced immune surveillance. Thus, oncogenesis is promoted.
• CD47 blocks calreticulin. This blocking mechanism seems to play a role in oncogenesis. Therefore, antibodies that block CD47 may be useful for carcinoma therapy (Chao MPet al. 2010).

Similar to calreticulin, calnexin is a chaperone that serves molecular protein control. However, in contrast to calreticulin, calnexin is membrane-bound.

1. Araki M et al (2020) The role of calreticulin mutations in myeloproliferative neoplasms. Int J Hematol 111:200-205.
2. Araki M et al (2017) Novel molecular mechanism of cellular transformation by a mutant molecular chaperone in myeloproliferative neoplasms. Cancer Sci 108:1907-1912.
3. Chao MPet al. (2010) Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Science Translational Medicine 2: 63ra94.
4. Fucikova J et al (2021) Calreticulin and cancer. Cell Res 31:5-16.