Receptor-mediated uptake of an extracellular Bcl-xL fusion protein inhibits apoptosis

AUTOR(ES)

Liu, Xiu-Huai

FONTE

The National Academy of Sciences

RESUMO

Bcl-xL, a member of the Bcl-2 family, inhibits many pathways of apoptosis when overexpressed in the cell cytosol. We examined the capacity of Bcl-xL fusion proteins to bind cells from the outside and block apoptosis. Full-length Bcl-xL protein at micromolar concentrations did not affect apoptosis when added to cell media. To increase uptake by cells, Bcl-xL was fused to the receptor-binding domain of diphtheria toxin (DTR). The Bcl-xL–DTR fusion protein blocked apoptosis induced by staurosporine, γ-irradiation, and poliovirus in a variety of cell types when added to media. The potency of inhibition of poliovirus-induced apoptosis by Bcl-xL–DTR was greater than that of strong caspase inhibitors. Brefeldin A, an inhibitor of vesicular traffic between the endoplasmic reticulum and Golgi apparatus, prevented the Bcl-xL–DTR blockade of apoptosis induced by staurosporine, suggesting that Bcl-xL–DTR must be endocytosed and reach intracellular compartments for activity. Many diseases are caused by overexpression or underexpression of Bcl-xL homologues. Extracellular delivery of Bcl-2 family member proteins may have a wide range of uses in promoting or preventing cell death.

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