Beschreibung:
<jats:p>Mutations in the<jats:italic>superoxide dismutase 1</jats:italic>(<jats:italic>SOD1</jats:italic>) gene contribute to motoneuron degeneration and are evident in 20% of familial amyotrophic lateral sclerosis cases. Mutant<jats:italic>SOD1</jats:italic>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<jats:italic>SOD1</jats:italic>-induced TLR-nuclear factor-κB (NF-κB) signaling in microglia.<jats:italic>bid</jats:italic>-deficient primary mouse microglia showed reduced NF-κB signaling in response to TLR4 activation or exposure to conditioned medium derived from<jats:italic>SOD1</jats:italic><jats:sup>G93A</jats:sup>expressing NSC-34 cells. Attenuation of NF-κB signaling in<jats:italic>bid-</jats:italic>deficient microglia was associated with lower levels of phosphorylated IKKα/β and p65, with a delayed degradation of IκBα 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-κB proinflammatory signaling during mutant<jats:italic>SOD1</jats:italic>-induced disease pathology.</jats:p><jats:p>Bid promotes TLR4-NF-κB signaling by interacting with TRAF6 and promoting TRAF6 K63-linked polyubiquitination in microglia.</jats:p>