The BNIP-2 and Cdc42GAP Homology/Sec14p-like domain of BNIP-Sα is a novel apoptosis-inducing sequence

Abstract

We have cloned the cDNAs for two novel human proteins, designated BNIP-Sα and β (for BNIP-2 Similar) that are homologous to BNIP-2, a previously known Bcl-2 and E1B-associated protein. The BNIP-S gene encodes two protein isoforms; the longer protein (BNIP-Sa) contains a complete BNIP-2 and Cdc42GAP Homology (BCH) domain, a novel protein domain that we recently identified, whereas its shorter variant (BNIP-Sβ) lacks the full BCH domain as a result of an alternative RNA splicing that introduces a nonsense intron. Primer-specific reverse-transcription PCR revealed that both BNIP-Sα and BNIP-Sβ mRNA are differentially expressed in various cells and tissues. The expression of BNIP-Sα or the complete BCH domain, but not BNIP-Sβ, causes extensive apoptosis in cells. Furthermore, BNIP-Sα can form a homophilic complex via a unique sequence motif within its BCH domain, and deletion of this interacting motif prevents its pro-apoptotic effect. These results indicate the presence of two BNIP-S splicing variants as cellular regulators and that the BCH domain of BNIP-Sα confers a novel apoptotic function. The significance of this is discussed.