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Glucose-regulated protein 78 (GRP78), an ER chaperone, is overexpressed in cancer cells. Solid tumor cells can secrete GRP78 that can promote tumor angiogenesis, differentiation of bone marrow-derived mesenchymal stem cells, tumor cell proliferation and polarization of tumor-associated macrophages. However, the mechanism by which GRP78 functions as a tumor promoter either by staying on the membrane to stimulate intracellular signals or directly entering into cytosolic remains unknown. Here, we reported that an endotoxin-free His-GRP78 protein was purified in vitro that simulates original secreted GRP78. Through analyzing GRP78 concentration in serum samples from 32 colon cancer patients, 40 nM His-GRP78 was selected as an optimized dose to treat cells. Biochemical analysis revealed that secreted GRP78 was able to enter into RAW264.7 and THP-1 cells directly rather than stay on the plasma membrane to transfer signals. Further studies showed that GRP78 internalization was endocytosis-dependent, and both phagocytosis and clathrin, caveolin-1 and micropinocytosis-mediated endocytosis pathways contributed to internalization of secreted GRP78 into cells. Mechanistically, Ajuba is able to interact with GRP78. Ablation of Ajuba suppressed the internalization of secreted GRP78 into cells, indicating that Ajuba was responsible for internalization of secreted GRP78 into RAW264.7. Furthermore, we observed that internalized GRP78 could entered into the mitochondrion and endoplasmic reticulum, which provided a suitable place and enough time for GRP78 to function in molecular and cellular processes. Together, these results reveal a novel mechanism by which secreted GRP78 internalizes into macrophages in the tumor microenvironment, which provides a potential target for drug development.

Ajuba receptor mediates the internalization of tumor-secreted GRP78 into macrophages through different endocytosis pathways