What is Glucose-regulated protein 78 (GRP78)?
Glucose-regulated protein 78 (GRP78) is a stress-inducible molecular chaperone expressed within the endoplasmic reticulum ("ER) where it acts as a master regulator of the unfolded protein response ("UPR") pathway.
The 78 kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone. GRP78 is a member of the 70 kDa heat shock family of proteins involved in correcting and clearing misfolded proteins in the ER. In response to cellular stress, GRP78 escapes from the ER and moves to the plasma membrane where it (a) functions as a receptor for many ligands, and (b) behaves as an autoantigen for autoantibodies that contribute to human disease and cancer.
→ Chaperones are proteins that guide proteins along the proper pathways for folding.
→ Endoplasmic reticulum is a network of membranes inside a cell through which proteins and other molecules move.
→ The unfolded protein response is the cells’ way of maintaining the balance of protein folding in the endoplasmic reticulum, which is the section of the cell designated for folding proteins with specific destinations such as other organelles or to be secreted by the cell.
At times of ER (= endoplasmic reticulum) stress, activation of the unfolded protein response, a multimolecular pathway, limits proteotoxicity (= a pathology that develops due to damaged or misfolded protein accumulations).
In malignancies, including multiple myeloma which is characterized by an accumulation of misfolded immunoglobulins, GRP78 expression is increased, with notable translocation of GRP78 to the cell surface. Studies suggest cell-surface GRP78 (csGRP78) to be of prognostic significance with emerging evidence that it interacts with a myriad of co-ligands to activate signaling pathways promoting cell proliferation and survival or apoptosis.
→ Cell surface GRP78 is preferably expressed in cancer cells and stressed endothelial cells
References:
Lemke MR, Glatzel M, Henneberg AE. Antimicroglia antibodies in sera of Alzheimer's disease patients. Biol Psychiatry. 1999 Feb 15;45(4):508-11. doi: 10.1016/s0006-3223(97)00456-3. PMID: 10071725.
Ninkovic S, Harrison SJ, Quach H. Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma. Expert Rev Hematol. 2020 Nov;13(11):1201-1210. doi: 10.1080/17474086.2020.1830372. Epub 2020 Oct 18. PMID: 32990063.
Slavisa Ninkovic, Simon J. Harrison & Hang Quach (2020) Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma, Expert Review of Hematology, 13:11, 1201-1210, DOI: 10.1080/17474086.2020.1830372
Xia, S., Duan, W., Liu, W. et al. GRP78 in lung cancer. J Transl Med 19, 118 (2021). https://doi.org/10.1186/s12967-021-02786-6
Gonzalez-Gronow, M, Gopal, U, Austin, RC, Pizzo, SV. Glucose-regulated protein (GRP78) is an important cell surface receptor for viral invasion, cancers, and neurological disorders. IUBMB Life. 2021; 73: 843– 854. https://doi.org/10.1002/iub.2502
Read A, Schröder M. The Unfolded Protein Response: An Overview. Biology (Basel). 2021 Apr 29;10(5):384. doi: 10.3390/biology10050384. PMID: 33946669; PMCID: PMC8146082.
Anti-Glucose regulated protein 78 (IgG + IgA)
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