Interaction of Calreticulin with CD40 Ligand, TRAIL and Fas Ligand

Abstract

The molecular chaperone calreticulin has been shown to bind C1q and mannan‐binding lectin (MBL), which are constituents of the innate immune defence system. C1q and MBL do not share a large sequence identity but have a similar overall molecular architecture: an N‐terminal triple‐helical collagen‐like domain and a C‐terminal globular domain with ligand‐binding properties. C1q is a hetero‐trimer, while MBL is a homo‐trimer, but due to the presence of N‐terminal cysteines they both form higher order oligomers of trimers, which are the mature functional molecules. The same molecular architecture is utilized by many other functionally diverse molecules and in this work the interaction of calreticulin with C1q and structurally similar molecules was investigated. In addition to C1q and MBL, CD40 ligand (CD40L), tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and Fas ligand (FasL) were found to bind calreticulin strongly. A low level or no binding was observed for adiponectin, tumour necrosis factor‐α (TNF‐α), CD30L, surfactant protein‐A and ‐D and collagen VIII. The interaction with calreticulin required a conformational change in CD40L, TRAIL and FasL and showed the same characteristics as calreticulin’s interaction with C1q and MBL: a time‐dependent saturable binding to immobilized protein, which was initially sensitive to salt but gradually developed into a salt‐insensitive interaction. Thus, the interaction requires a structural change in the interaction partner and leads to a conformational change in calreticulin itself. The implications of these results are that calreticulin may function as a general response modifier for a whole group of immunologically important proteins.

Immunogenic cancer cell death: a key-lock paradigm

“…CRT is a 'sticky' protein and it reportedly interacts with the soluble serum proteins thrombospondin as well as the complement factor C1q, both of which may serve as 'bridges' to facilitate the recognition of CRT by phagocytes [27]. On theoretical grounds, the receptor(s) of CRT on DC might be CD91 [12], scavenger receptor A (SR-A), scavenger receptor expressed by endothelial cell-I (SREC-I) [28], or CD40 ligand, TRAIL or Fas ligand [29], which all have been shown to interact with CRT and/or to mediate the phagocytic recognition of CRTexposing cells (Figure 3). Systematic knockout studies should evaluate which among these receptors is required for mounting a productive immune response against dying cells.…”

Prerequisites for the Antitumor Vaccine-Like Effect of Chemotherapy and Radiotherapy

“…Possible candidates include the major CRT receptor CD91 as well as other CRT-interacting proteins such as scavenger receptor A, scavenger receptor expressed on endothelial cell I, 22 CD40 ligand, tumor necrosis factorYrelated apoptosisinducing ligand (tumor necrosis factorYrelated apoptosis inducing ligand), or CD95/FAS ligand. 23 The CRT-driven uptake of tumor antigens by DCs is per se insufficient to elicit an antitumor immune response as internalized antigens must be processed and re-exposed for the cross-priming of CD4+ and CD8+ T lymphocytes. This implies that other signaling pathways are involved in ICD.…”

The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death

“…The receptor of CRT on DC is also elusive, yet it might include scavenger receptor A, scavenger receptor expressed by endothelial cell-I, 17 CD91 18 or many other molecules such as CD40 ligand, TRAIL and Fas ligand. 19 ERp57, which tightly binds to CRT in the ER lumen, 11 catalyzes disulfide oxidation, isomerization and reduction of native glycoproteins. ERp57 is also an integral component of the peptide-loading complex of the major histocompatibility complex (MHC) class I pathway.…”