GRP78 targeting: Hitting two birds with a stone

Abstract

Background: Glucose regulating protein 78 (GRP78) is one member of the Heat Shock Protein family of chaperone proteins (HSPA5) found in eukaryotes. It acts as the master of the Unfolded Protein Response (UPR) process in the lumen of the Endoplasmic Reticulum (ER).

Scope: Under the stress of unfolded proteins, GRP78 binds to the unfolded proteins to prevent misfolding, while under the load of the unfolded protein, it drives the cell to autophagy or apoptosis. Several attempts reported the overexpression of GRP78 on the cell membrane of cancer cells and cells infected with viruses or fungi.

Major conclusions: Cell-surface GRP78 is used as a cancer cell target in previous studies. Additionally, GRP78 is used as a drug target to stop the progression of cancer cells by different compounds, including peptides, antibodies, and some natural compounds. Additionally, it can be used as a protein target to reduce the infectivity of different viruses, including the pandemic SARS-CoV-2. Besides, GRP78 targeting is used in diagnosis and imaging modalities using radionuclides.

General significance: This review summarizes the various attempts that used GRP78 both in therapy (fighting cancer, viral and fungal infections) and diagnosis (imaging).

Keywords: BiP; Cancer-targeting; GRP78; Natural compounds; Peptide inhibitors; SARS-CoV-2.

Graphical abstract

Fig. 1

Functional aspect of GRP78 in normal versus stress condition. In normal state (left), the GRP78 is located in the lumen of the endoplasmic reticulum (ER) bound to and inactivating ATF6 (blue triangle), PERK (red circle), and IRE1 (yellow square) enzymes. In the stress condition (right), the enzymes are free to do their jobs. ATF6 is translocated to Golgi apparatus to be cleaved then again translocated to the nucleus and helps in upregulating chaperones such as GRP78. PERK inhibits the translation and protein synthesis while IRE1 enhances the folding and ERAD. Under the pressure of the unfolded proteins, the GRP78 escapes the ER retention and translocate to the cytoplasm and the cell membrane. CS-GRP78 is subjected to the recognition of pathogenic proteins (Spike and envelope viral protein and coat proteins of fungi). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)