| First Author | Yan J | Year | 2018 |
| Journal | Cell Res | Volume | 28 |
| Issue | 7 | Pages | 701-718 |
| PubMed ID | 29795446 | Mgi Jnum | J:288217 |
| Mgi Id | MGI:6430867 | Doi | 10.1038/s41422-018-0041-7 |
| Citation | Yan J, et al. (2018) The BH3-only protein BAD mediates TNFalpha cytotoxicity despite concurrent activation of IKK and NF-kappaB in septic shock. Cell Res 28(7):701-718 |
| abstractText | The inflammatory cytokine TNFalpha plays a crucial role in the pathology of many inflammatory and infectious diseases. However, the mechanism underlying TNFalpha cytotoxicity in these diseases is incompletely understood. Here we report that the pro-apoptotic BCL-2 family member BAD mediates TNFalpha cytotoxicity despite concurrent activation of IKK and NF-kappaB in vitro by inducing apoptosis in cultured cells and in vivo by eliciting tissue damage of multiple organs and contributing to mortality in septic shock. At high doses, TNFalpha significantly inactivates RhoA through activation of the Src-p190GAP pathway, resulting in massive actin stress fiber destabilization, followed by substantial BAD release from the cytoskeleton to the cytosol. Under this condition, activated IKK fails to phosphorylate all cytosolic BAD, allowing translocation of non-phosphorylated BAD to mitochondria to trigger apoptosis. Polymicrobial infection utilizes the same mechanism as high-dose TNFalpha to elicit apoptosis-associated tissue damage of multiple organs. Consequently, loss of Bad or elimination of BAD pro-apoptotic activity protects mice from tissue damage of multiple organs and reduces mortality rates. Our results support a model in which BAD mediates TNFalpha cytotoxicity despite concurrent activation of the IKK-NF-kappaB pathway in cultured mammalian cells and in septic shock. |
