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Sci. STKE, 14 January 2003
Vol. 2003, Issue 165, p. tw22
[DOI: 10.1126/stke.2003.165.tw22]


Apoptosis Immunophilin Directs Bcl Proteins to the Mitochondria

The antiapoptotic proteins Bcl-2 and Bcl-xL block the mitochondrial route to apoptosis by localizing to the mitochondria to prevent the release of proapoptotic proteins that drive apopotosome assembly and caspase activation. But just how Bcl-2 and Bcl-xL are targeted to the mitochondria has not been clear. Shirane and Nakayama show that both Bcl-2 and Bcl-xL associate with a member of the FKBP family of immunophilins called FKBP38. The interaction is required for the mitochondrial localization of both Bcl proteins and, hence, their anti-apoptotic activity. The endogenous proteins also colocalize at the mitochondria. Unlike other immunophilins, FKBP38 does not require association with the immunosuppressant molecule FK506 to inhibit calcineurin, a phosphatase implicated in cell death regulation. Overexpression of FKB38 in mammalian cells promoted mitochondrial localization of Bcl-2 and Bcl-xL and reduced apoptosis in response to various proapoptotic stimuli. Reduction of FKBP38 expression by RNA interference altered the localization of Bcl-2 and Bcl-xL and increased cell sensitivity to apoptosis. Because other immunophilins regulate localization of glucocorticoid receptors to the nucleus, it possible that immunophilins in general mediate intracellular protein transport.

M. Shirane, K.I. Nakayama, Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nature Cell Biol. 5, 1-10 (2003). [Online Journal]

Citation: Immunophilin Directs Bcl Proteins to the Mitochondria. Sci. STKE 2003, tw22 (2003).

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