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Review
. 2022 May 24;10(6):1222.
doi: 10.3390/biomedicines10061222.

Physiological Roles of the Autoantibodies to the 78-Kilodalton Glucose-Regulated Protein (GRP78) in Cancer and Autoimmune Diseases

Mario Gonzalez-Gronow  1 , Salvatore Vincent Pizzo  1
Affiliations
Review

Physiological Roles of the Autoantibodies to the 78-Kilodalton Glucose-Regulated Protein (GRP78) in Cancer and Autoimmune Diseases

Mario Gonzalez-Gronow et al. Biomedicines. .

Abstract

The 78 kDa glucose-regulated protein (GRP78), a member of the 70 kDa heat-shock family of molecular chaperones (HSP70), is essential for the regulation of the unfolded protein response (UPR) resulting from cellular endoplasmic reticulum (ER) stress. During ER stress, GRP78 evades retention mechanisms and is translocated to the cell surface (csGRP78) where it functions as an autoantigen. Autoantibodies to GRP78 appear in prostate, ovarian, gastric, malignant melanoma, and colorectal cancers. They are also found in autoimmune pathologies such as rheumatoid arthritis (RA), neuromyelitis optica (NMO), anti-myelin oligodendrocyte glycoprotein antibody-associated disorder (AMOGAD), Lambert-Eaton myasthenic syndrome (LEMS), multiple sclerosis (MS), neuropsychiatric systemic lupus erythematosus (NPSLE) and type 1 diabetes (T1D). In NMO, MS, and NPSLE these autoantibodies disrupt and move across the blood-brain barrier (BBB), facilitating their entry and that of other pathogenic antibodies to the brain. Although csGRP78 is common in both cancer and autoimmune diseases, there are major differences in the specificity of its autoantibodies. Here, we discuss how ER mechanisms modulate csGRP78 antigenicity and the production of autoantibodies, permitting this chaperone to function as a dual compartmentalized receptor with independent signaling pathways that promote either pro-proliferative or apoptotic signaling, depending on whether the autoantibodies bind csGRP78 N- or C-terminal regions.

Keywords: ER dysfunctions; GRP78 N-glycosylation; GRP78 autoantigenicity; GRP78 cell surface compartments; GRP78 citrullination; autoimmune diseases; cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the anti-GRP78 IgG molecular structure and its associated N-glycan structures identified in cancer patients. It consists of two interconnected heavy (H) and two light chains (L) with two domains that infer different properties, the fragment antigen-binding (Fab) and fragment crystallizable (Fc) domains. The Fab domain is responsible for recognizing and binding the antigen. The Fc domain contains two glycans attached to Asn297 in conserved regions of the CH2 domain. The Fc domain binds to the FcR on natural killers and other inflammatory cells. In cancer, the Fab region is asymmetrically glycosylated with one additional N-glycan that converts the anti-GRP78 IgG into a univalent molecule that binds the antigen with a decreased affinity, preventing it from triggering some IgG-linked functions of the immune response such as complement fixation, phagocytic activity and antigen clearance. Moreover, the N-glycans of the Fc region are aberrantly glycosylated, mainly at the levels of D-mannosylation and galactosylation with a reduction in the affinity of the antibody for the FcR and its activation, thus inhibiting the inflammatory effects of the IgG.
Figure 2
Figure 2
Model of the mechanism of BBB opening induced by GRP78 antibodies common to NMO, AMOGAD, LEMS and SLE. The binding of antibodies to GRP78 on the surface of BBB-endothelial cells induces the activation of NF-κB signaling pathways that disrupt the tight junction enhancing the diffusion of pathogenic antibodies into the brain. Astrocytes react with AQP4-Abs in NMO, while oligodendrocytes react with pathogenic anti-myelin Abs in AMOGAD. Pathogenic antibodies to brain antigens found in LEMS and SLE may also function through this mechanism to induce the damage observed in these pathologies.
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