Abstract

Calreticulin (CRT), initially described as an endoplasmic reticulum (ER)-resident chaperone with high affinity for Ca2+, also localizes in the nucleus, cytoplasm, plasma membrane and the extracellular medium, suggesting multifunctional roles in different systems and cell types. Cell surface (ecto-CRT) and extracellular CRT have been found driving diverse processes and, therefore, CRT is now associated to several diseases. Here, we explore the current knowledge relating extracellular CRT to human pathologies, focusing on cancer, rheumatoid arthritis, systemic lupus erythematosus, wound repair and the retroviral infection with human T-cell lymphotropic virus type 1 (HTLV-1). In cancer, CRT shows immunomodulatory functions by exposing to the cell surface of dying cells, acting as a critical danger pattern for the recognition and engulfment of tumor cells. Cell surface CRT is relevant for the immunological clearance of tumors induced by some chemotherapeutic and physical agents, a process called “immunogenic cell death” (ICD), characterized by rapid translocation of CRT to the surface and/or its release to the extracellular space. Among novel antitumor treatments, a combination of ICD inducers together with immune checkpoint inhibitors have shown effective synergistic effects against resistant tumors. In autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, the increased CRT serum levels and the presence of anti-CRT autoantibodies are common and may be involved in the disease progression. It has been found that cell surface CRT mediates cell signaling associated to main risk factors in patients with rheumatoid arthritis, suggesting key extracellular functions contributing to autoimmune pathogenesis. In vitro studies and animal models show that wound treatment with exogenous CRT increase epithelization rate via migration of keratinocytes and formation of new epidermis by fibroblasts, which are required for successful wound repair. Secretion of CRT has also been found in HTLV-1-infected lymphocytes from patients with spastic paraparesis. ER CRT interacts with two viral proteins, p12I and Tax, which affect viral replication and survival. The CRT-Tax interaction may promote CRT secretion and potentially block the extracellular deleterious effects of the viral infection. CRT association to disease not only serves as a biomarker of disease progression, but also extracellular CRT emerges as a potential therapeutic target and drug. The variety of processes involving extracellular CRT opens new treatment possibilities in multifactorial diseases, such as cancer and autoimmune disorders.