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.