Kinsella, Sinéad König, Hans-Georg Prehn, Jochen HM Bid Promotes K63-Linked Polyubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) and Sensitizes to Mutant SOD1-Induced Proinflammatory Signaling in Microglia. <p>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-κB (NF-κB) signaling in microglia. bid-deficient primary mouse microglia showed reduced NF-κB signaling in response to TLR4 activation or exposure to conditioned medium derived from SOD1 (G93A) expressing NSC-34 cells. Attenuation of NF-κB signaling in bid-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 SOD1-induced disease pathology. Bid promotes TLR4-NF-κB signaling by interacting with TRAF6 and promoting TRAF6 K63-linked polyubiquitination in microglia.</p> Animals;BH3 Interacting Domain Death Agonist Protein;Cells;Cultured;Coculture Techniques;Culture Media;Conditioned;Female;Gene Expression Regulation;Humans;I-kappa B Kinase;Lipopolysaccharides;Male;Mice;Inbred C57BL;Transgenic;Microglia;Mutation;Phosphatidylcholines;Signal Transduction;Superoxide Dismutase;TNF Receptor-Associated Factor 6;Toll-Like Receptor 4;Ubiquitination;Physiology;Medical Physics 2019-11-22
    https://repository.rcsi.com/articles/journal_contribution/Bid_Promotes_K63-Linked_Polyubiquitination_of_Tumor_Necrosis_Factor_Receptor_Associated_Factor_6_TRAF6_and_Sensitizes_to_Mutant_SOD1-Induced_Proinflammatory_Signaling_in_Microglia_/10793873