Characterization of a novel alternatively spliced human transcript encoding an N-terminally truncated Vps24 protein that suppresses the effects of Bax in an ESCRT independent manner in yeast.

Elucidating novel anti-apoptotic regulatory pathways is central to further understanding the molecular basis of several pathologies, including cancer. We have previously reported the identification of several mammalian cDNAs effective in preventing the lethal effects of heterologous expression of a pro-apoptotic BAX cDNA in yeast [Yang, Z., Khoury, C., Jean-Baptiste, G., Greenwood, M.T., 2006. Identification of mouse sphingomyelin synthase 1 (SMS1) as a suppressor of Bax mediated cell death in yeast. FEMS Yeast Res. 6, 751-762]. Here we report that one of the Bax suppressors encodes a novel 156 amino acid variant of the human Vps24 protein, Vps24beta, that lacks the N-terminal lipid binding domain of the well characterized 222 residue Vps24 (Vps24alpha). We demonstrate that the VPS24beta cDNA represents an expressed transcript that is likely produced by alternative splicing of the human VPS24 gene. Vps24alpha, but not Vps24beta, prevented the temperature and salt sensitive growth defects observed in a yeast mutant lacking a functional VPS24 gene. In contrast, Vps24beta, but not Vps24alpha, suppressed the inhibitory effects of Bax on yeast growth. Vps24beta protein also suppressed the effects of Bax in mutants lacking other VPS genes suggesting that a functional ESCRT pathway, of which the yeast Vps24p is an essential component, is not required for Vps24beta function. Taken together, we demonstrate that the human VPS24 gene gives rise to two functionally distinct proteins, one of which is involved in the ESCRT pathway and another novel protein that serves an anti-apoptotic role.