| First Author | Chen Y | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 22 | Pages | 15455-65 |
| PubMed ID | 23603904 | Mgi Jnum | J:199612 |
| Mgi Id | MGI:5503282 | Doi | 10.1074/jbc.M113.452342 |
| Citation | Chen Y, et al. (2013) A nucleus-targeted alternately spliced Nix/Bnip3L protein isoform modifies nuclear factor kappaB (NFkappaB)-mediated cardiac transcription. J Biol Chem 288(22):15455-65 |
| abstractText | Several Bcl2 family proteins are expressed both as mitochondrial-targeted full-length and as cytosolic truncated alternately spliced isoforms. Recombinantly expressed shorter Bcl2 family isoforms can heterotypically bind to and prevent mitochondrial localization of their full-length analogs, thus suppressing their activity by sequestration. This "sponge" role requires 1:1 expression stoichiometry; absent this an alternate role is suggested. Here, RNA sequencing revealed coordinate regulation of BH3-only protein Nix/Bnip3L (Nix) and its alternately spliced soluble form (sNix) in hearts, but relative sNix/Nix expression of approximately 1:10. Accordingly, we examined other putative functions of sNix. Although Nix expressed in H9c2 rat myoblasts localized to mitochondria, sNix showed variable cytoplasmic and nuclear distribution. Tumor necrosis factor alpha (TNFalpha) induced rapid and complete sNix nucleoplasmic translocation concomitant with nuclear translocation of the p65/RelA subunit of NFkappaB. sNix co-localized and co-precipitated with p65/RelA after TNFalpha stimulation; TNFalpha-induced sNix nuclear translocation did not occur in p65/RelA null murine embryonic fibroblasts. ChIP sequencing of TNFalpha-stimulated H9c2 cells revealed sNix suppression of p65/RelA binding to a subset of weaker DNA binding sites, accounting for its ability to alter gene expression in cultured cells and in vivo mouse hearts. These findings reveal TNFalpha-stimulated cytoplasmic-nuclear shuttling of the alternately spliced non-mitochondrial Nix isoform and uncover a role for sNix as a modulator of TNFalpha/NFkappaB-stimulated cardiac gene expression. Transcriptional co-regulation of sNix and Nix, combined with sNix posttranslational regulation by TNFalpha, comprises a previously unknown mechanism for molecular cross-talk between extrinsic death receptor and intrinsic mitochondrial apoptosis pathways. |
