GRP78: Introduction

The 78 kDa glucose-regulated protein 78 (Grp78), also known as immunoglobulin heavy-chain binding protein or binding-immunoglobulin protein (BiP), is a multifunctional protein which belongs to the huge HSP70 family of molecular chaperones 1, 2.  Grp78/BiP is constitutively expressed in the ER lumen where it assists in ER proteostasis which is critically involved in the folding and trafficking of secretory and transmembrane proteins 3. Interestingly, the expression of Grp78/BiP is induced  upon exposure to ageing-related, environmental or genetic stressors culminating in the aggregation of misfolded proteins and the dysfunction of protein homeostasis in the ER 4. Current data provide evidence for a novel homeostatic function of Grp78/BiP in mediating lipid metabolism 5.

Grp78/BiP is a key regulator of the unfolded protein response (UPR) which is induced in the cells upon ER stress. Despite its well established function in the UPR, Grp78/BiP is also a regulator for calcium homeostasis in the ER, a coordinator of ER-associated protein degradation (ERAD) across the ER membrane, a mediator of macroautophagy, and an activator of pro-survival pathways. Grp78/BiP can be found not only in the lumen and membrane of the ER, but also in the cytosol, nucleus, mitochondria, the plasma membrane or the extracellular milieu including exosomes 6-10. While cell surface-associated Grp78/BiP has been found to exert cytoprotection and to mediate cytoskeletal remodeling 11, secreted Grp78/BiP exerts immunomodulatory functions 12. Moreover, cell surface Grp78/BiP is known to function as a receptor or co-receptor for numerous ligands, activating signaling cascades involved in tumor cell survival and proliferation as well as in the development of chemoresistance. As a key regulator of ER function, Grp78/BiP is not only associated with cancer, but also with ageing and age-dependent disorders, neurodegenerative diseases, autoimmunity and autoinflammatory diseases, cardiovascular diseases, and microbial infections. Targeting Grp78/BiP in certain cancers is being evolved  into an excellent therapeutic tool in malignity and hold promise for application in other disorders. Herein, the biology of Grp78/BiP and its role in disease and therapy is compiled.