Calreticulin: non‐endoplasmic reticulum functions in physiology and disease

Abstract

Calreticulin (CRT), when localized to the endoplasmic reticulum (ER), has important functions in directing proper conformation of proteins and glycoproteins, as well as in homeostatic control of cytosolic and ER calcium levels. There is also steadily accumulating evidence for diverse roles for CRT localized outside the ER, including data suggesting important roles for CRT localized to the outer cell surface of a variety of cell types, in the cytosol, and in the extracellular matrix (ECM). Furthermore, the addition of exogenous CRT rescues numerous CRT-driven functions, such as adhesion, migration, phagocytosis, and immunoregulatory functions of CRT-null cells. Recent studies show that topically applied CRT has diverse and profound biological effects that enhance cutaneous wound healing in animal models. This evidence for extracellular bioactivities of CRT has provided new insights into this classically ER-resident protein, despite a lack of knowledge of how CRT exits from the ER to the cell surface or how it is released into the extracellular milieu. Nonetheless, it has become clear that CRT is a multicompartmental protein that regulates a wide array of cellular responses important in physiological and pathological processes, such as wound healing, the immune response, fibrosis, and cancer.-Gold, L. I., Eggleton, P., Sweetwyne, M. T., Van Duyn, L. B., Greives, M. R., Naylor, S.-M., Michalak, M., Murphy-Ullrich, J. E. Calreticulin: non-endoplamic reticulum functions in physiology and disease.

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

“…CRT is well-known as a calcium-binding chaperone protein mainly located in the endoplasmic reticulum, involved in calcium homoeostasis and in the folding of newly synthesized proteins (10). CRT also plays a role in many other biological systems, including functions outside the endoplasmic reticulum, indicating that the protein is a multiprocess molecule (29). Its involvement in the recognition and immunogenicity of apoptotic cells has recently been elucidated (11).…”

CALR mutations in myeloproliferative neoplasms: Hidden behind the reticulum

“…Calreticulin (CALR) is a developmentally highly conserved, multicompartmental and multifunctional protein best known for its role as a Ca 21 binding chaperone in the endoplasmic reticulum (ER) lumen [5]. The CALR-1 gene (the product of calreticulin-2 has only been detected in the testis) is located on human chromosome 19 and mouse chromosome 8, spanning 4.6 and 3.6 kb, respectively, and contains nine exons with a highly conserved sequence (96% amino acid identity) between human and mouse.…”

“…In addition to canonical ER related functions, CALR is reported to be found in the cytosol, nucleus, at the cell surface as well as extracellularly, where it accomplishes multiple functions as a critical mediator of physiological and pathological processes such as the immune response, proliferation and apoptosis, cell phagocytosis, wound healing, and fibrosis [5]. Of interest, upregulation of CALR on the cell surface of leukemia blasts and dysplastic progenitors of MDS has been reported to be involved in an "eat me" signal thereby affecting the phagocytosis of neoplastic cells.…”

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

“…CRT also is a multifunctional protein that is present in numerous cellular compartments, including the ER, cytoplasm, nucleus, at the cell surface, and as a released protein (1)(2)(3)(4)(5). There is evidence to suggest the involvement of CRT in tissue remodeling and wound healing.…”