Pro-apoptotic activity of mBNIP-21 depends on its BNIP-2 and Cdc42GAP homology (BCH) domain and is enhanced by coxsackievirus B3 infection.

Our previous study reported that mouse BNIP-21 (mBNIP-21) induces apoptosis through a mitochondria-dependent pathway. To map the functional domains of mBNIP-21, we performed mutational analyses and demonstrated that the BNIP-2 and Cdc42GAP homology (BCH) domain is required for apoptosis induction by mBNIP-21 targeting the mitochondria and inducing cytochrome c release. This pro-apoptotic activity was enhanced by coxsackievirus infection. However, deletion of the Bcl-2 homology 3 (BH3)-like domain, a well-known cell 'death domain' in proapoptotic Bcl-2 family proteins, did not affect the activity of mBNIP-21. These data were further supported by transfection of a mouse Bax (mBax) mutant, whose BH3 was replaced by the mBNIP-21 BH3-like domain. This replacement significantly reduced the pro-apoptotic activity of mBax. We also found that the predicted calcium binding domain has no contribution to the mBNIP-21-induced apoptosis. Further mapping of the motifs of BCH domain demonstrated that deletion of the hydrophobic motif proximal to the C-terminal of the BCH significantly reduced its proapoptotic activity. These findings suggest that mBNIP-21, as a member of the BNIP subgroup of the Bcl-2-related proteins, functions without need of BH3 but its BCH domain is critical for its activity in inducing cell elongation, membrane protrusions and apoptotic cell death.

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