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Review
. 2019 Jun 1:226:156-163.
doi: 10.1016/j.lfs.2019.04.022. Epub 2019 Apr 9.

GRP78: A cell's response to stress

Ibrahim M Ibrahim  1 , Doaa H Abdelmalek  1 , Abdo A Elfiky  2
Affiliations
Review

GRP78: A cell's response to stress

Ibrahim M Ibrahim et al. Life Sci. .

Abstract

Background: Glucose-Regulated Protein 78 (GRP78) is a chaperone heat shock protein that has been intensely studied in the last two decades. GRP78 is the master of the unfolded protein response (UBR) in the Endoplasmic Reticulum (ER) in normal cells. GRP78 force the unfolded proteins to refold or degrade using cellular degradation mechanisms.

Scope: Under stress, the overexpression of GRP78 on the cell membrane mediates the vast amount of disordered proteins. Unfortunately, this makes it a tool for pathogens (bacterial, fungal and viral) to enter the cell and to start different pathways leading to pathogenesis. Additionally, GRP78 is overexpressed on the membranes of various cancer cells and increase the aggressiveness of the disease.

Major conclusions: The current review summarizes structure, function, and different mechanisms GRP78 mediate in response to normal or stress conditions.

General significance: GRP78 targeting and possible inhibition mechanisms are also covered in the present review aiming to prevent the virulence of pathogens and cancer.

Keywords: GRP78; HSP70; Heat shock proteins; Membrane receptors; Stress; Unfolded protein response.

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Figures

Unlabelled Image
Graphical abstract
Fig. 1
Fig. 1
A) shows the x-ray apo form of GRP78 solved structure (PDB ID 6EOC) at 1.67 Å resolution. The protein is represented by cartoon colored green (NBD), red (SBD) and purple (linker). GRP78 sequence is represented also with the same color as the protein domains. B) ATP binding domain with pound ATP molecule (PDB ID 5F1X) at 1.90 Å resolution represented as the rainbow-colored cartoon. The binding site with ATP is enlarged to show the amino acids involved in the interaction. PyMOL software is used to represent the entire figure [127]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Illustration showing the cell in response to a stress condition. Accumulated unfolded proteins make activation of PERK, IRE1, and ATF6 which induce overexpression of GRP78 and other chaperone proteins. GRP78 may be cell surface expressed making the stressed cell susceptible to pathogens (viral or fungal). Besides, if the cell is cancerous, CS GRP78 will induce resistance to chemotherapy.
See this image and copyright information in PMC

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