| First Author | Kinsella S | Year | 2016 |
| Journal | eNeuro | Volume | 3 |
| Issue | 2 | PubMed ID | 27257617 |
| Mgi Jnum | J:240199 | Mgi Id | MGI:5882645 |
| Doi | 10.1523/ENEURO.0099-15.2016 | Citation | Kinsella S, et al. (2016) Bid Promotes K63-Linked Polyubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) and Sensitizes to Mutant SOD1-Induced Proinflammatory Signaling in Microglia. eNeuro 3(2):ENEURO.0099-15.2016 |
| abstractText | Mutations in the superoxide dismutase 1 (SOD1) gene contribute to motoneuron degeneration and are evident in 20% of familial amyotrophic lateral sclerosis cases. Mutant SOD1 induces microglial activation through a stimulation of Toll-like receptors 2 and 4 (TLR2 and TLR4). In the present study, we identified the proapoptotic Bcl-2 family protein Bid as a positive regulator of mutant SOD1-induced TLR-nuclear factor-kappaB (NF-kappaB) signaling in microglia. bid-deficient primary mouse microglia showed reduced NF-kappaB signaling in response to TLR4 activation or exposure to conditioned medium derived from SOD1 (G93A) expressing NSC-34 cells. Attenuation of NF-kappaB signaling in bid-deficient microglia was associated with lower levels of phosphorylated IKKalpha/beta and p65, with a delayed degradation of IkappaBalpha and enhanced degradation of Peli1. Upstream of IKK, we found that Bid interacted with, and promoted, the K63-linked polyubiquitination of the E3 ubiquitin ligase tumor necrosis factor receptor associated factor 6 (TRAF6) in microglia. Our study suggests a key role for Bid in the regulation of TLR4-NF-kappaB proinflammatory signaling during mutant SOD1-induced disease pathology. Bid promotes TLR4-NF-kappaB signaling by interacting with TRAF6 and promoting TRAF6 K63-linked polyubiquitination in microglia. |
