GRP78 at the Centre of the Stage in Cancer and Neuroprotection

Abstract

The 78-kDa glucose-regulated protein GRP78, also known as BiP and HSP5a, is a multifunctional protein with activities far beyond its well-known role in the unfolded protein response (UPR) which is activated after endoplasmic reticulum (ER) stress in the cells. Most of these newly discovered activities depend on its position within the cell. GRP78 is located mainly in the ER, but it has also been observed in the cytoplasm, the mitochondria, the nucleus, the plasma membrane, and secreted, although it is dedicated mostly to engage endogenous cytoprotective processes. Hence, GRP78 may control either UPR and macroautophagy or may activated phosphatidylinositol 3-kinase (PI3K)/AKT pro-survival pathways. GRP78 influences how tumor cells survive, proliferate, and develop chemoresistance. In neurodegeneration, endogenous mechanisms of neuroprotection are frequently insufficient or dysregulated. Lessons from tumor biology may give us clues about how boosting endogenous neuroprotective mechanisms in age-related neurodegeneration. Herein, the functions of GRP78 are revealed at the center of the stage of apparently opposite sites of the same coin regarding cytoprotection: neurodegeneration and cancer. The goal is to give a comprehensive and critical review that may serve to guide future experiments to identify interventions that will enhance neuroprotection.

Keywords: BiP; ER stress; ERAD; GRP78; autophagy; endogenous mechanisms; neurodegeneration; neuroprotection.

Figure 1

Graphical summary of the regulation and activities promoted by GRP78 within a cell. Induction and regulation of the transcription of the HSP5a gene is mediated by several transcription factors that bind to ERSE or CREB motifs in the promoter of the gene. Alternative processing of its pre-mRNA can occur under stressful conditions leading to retention of intron 1 (yellow line) that advance an stop codon, giving to GRP78va truncated protein that is retained in the cytosol because it lacks the ER-signaling motif (purple triangle). Commonly processing GRP78 is submitted under post-transcriptional regulation either due to the action of factors on its IRES motif or by the action of different miRNAs. GRP78 is found mainly in the luminal ER where it can promote the activation of the UPR, ERAD, or MAM regulation. In some circumstances, GRP78 can be translocated to the cell surface where it can interact to multiple partners and hence modulate different pathways. It is also be secreted where it can immunomodulate.