GRP78 is a novel receptor initiating a vascular barrier protective response to oxidized phospholipids

Birukova, Anna A.; Singleton, Patrick A.; Gawlak, Grzegorz; Tian, Xinxin; Mirzapoiazova, Tamara; Mambetsariev, Bolot; Dubrovskyi, Oleksii; Oskolkova, Olga; Bochkov, Valery N.; Birukov, Konstantin G.

doi:10.1091/mbc.e13-12-0743

Cited by 50 publications

(41 citation statements)

References 48 publications

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“…The work presented here identifies an additional pathway upstream of GPX4 by HSPA5 to limit lipid peroxidation and underscores the importance of molecular chaperones in ferroptosis (12). Similar to previous studies conducted with endothelial (31) and glial cells (32), the current study demonstrates that HSPA5 plays a role in regulating lipid peroxidation in PDAC cells. Inhibition of lipid peroxidation by antioxidants (e.g., ferrostatin-1 (4) and liprostatin-1 (7)) diminishes erastin-induced ferroptosis in HSPA5-kncodown PDAC cells.…”

Section: Discussionsupporting

confidence: 89%

HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

et al. 2017

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Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here we show that heat shock 70kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacological inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis in vitro and in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance.

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Section: Discussionsupporting

confidence: 89%

HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

et al. 2017

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“…Because plasma membranes of malignant cells, but not nontumor cells, express high levels of cell surface GRP78 in vivo, GRP78 has been proposed as a cancer therapeutic target (36). Cell surface expression of GRP78 in human lung MECs or HUVECs has been described, but no consistent relationship to endothelial integrity has been reported (37, 38). …”

Section: Discussionmentioning

confidence: 99%

Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica

et al. 2017

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Neuromyelitis optica (NMO) is an inflammatory disorder mediated by antibodies to aquaporin-4 (AQP4) with prominent blood-brain barrier (BBB) breakdown in the acute phase of the disease. Anti-AQP4 antibodies are produced mainly in the periphery, yet they target the astrocyte perivascular end feet behind the BBB. We reasoned that an endothelial cell–targeted autoantibody might promote BBB transit of AQP4 antibodies and facilitate NMO attacks. Using monoclonal recombinant antibodies (rAbs) from patients with NMO, we identified two that strongly bound to the brain microvascular endothelial cells (BMECs). Exposure of BMECs to these rAbs resulted in nuclear translocation of nuclear factor κB p65, decreased claudin-5 protein expression, and enhanced transit of macromolecules. Unbiased membrane proteomics identified glucose-regulated protein 78 (GRP78) as the rAb target. Using immobilized GRP78 to deplete GRP78 antibodies from pooled total immunoglobulin G (IgG) of 50 NMO patients (NMO-IgG) reduced the biological effect of NMO-IgG on BMECs. GRP78 was expressed on the surface of murine BMECs in vivo, and repeated administration of a GRP78-specific rAb caused extravasation of serum albumin, IgG, and fibrinogen into mouse brains. Our results identify GRP78 antibodies as a potential component of NMO pathogenesis and GRP78 as a candidate target for promoting central nervous system transit of therapeutic antibodies.

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“…GRP78 can be translocated and anchored to the cell surface by binding to the ER-co-chaperone HTJ-1/MTJ-1 (Birukova et al, 2014; Figure 1). The translocation is promoted by accumulation of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC), a phospholipid that directly interacts with GRP78, induces membrane accumulation of the GRP78/HTJ-1 complex and its targeting to caveolin-enriched microdomains (Birukova et al, 2014). Once the complex is at the membrane, it activates Src/Fyn kinase leading to assembly of the PI3K complex and activation of mTOR and sphingosine-1-phosphate receptor 1.…”

Section: Grp78 a Very Important Protein With Multiple Functions In Mmentioning

confidence: 99%

GRP78 at the Centre of the Stage in Cancer and Neuroprotection

2017

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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.

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GRP78 is a novel receptor initiating a vascular barrier protective response to oxidized phospholipids

Cited by 50 publications

References 48 publications

HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica

GRP78 at the Centre of the Stage in Cancer and Neuroprotection

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