TY - JOUR T1 - Bid promotes K63-linked polyubiquitination of tumour necrosis factor (α) receptor adaptor protein 6 (TRAF6) and sensitizes to mutant SOD1 – induced proinflammatory signalling in microglia JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0099-15.2016 SP - ENEURO.0099-15.2016 AU - Sinéad Kinsella AU - Hans-Georg König AU - Jochen H.M. Prehn Y1 - 2016/05/02 UR - http://www.eneuro.org/content/early/2016/05/02/ENEURO.0099-15.2016.abstract N2 - Mutations in the Superoxide dismutase (SOD1) gene contribute to motoneuron degeneration and are evident in 20% of familial ALS 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 pro-apoptotic Bcl-2 family protein Bid as a positive regulator of mutant SOD1-induced TLR – Nuclear Factor-κB (NF-κB) signalling in microglia. bid-deficient primary mouse microglia showed reduced NF-κB signalling in response to TLR4 activation or exposure to conditioned medium derived from SOD1G93A expressing NSC-34 cells. Attenuation of NF-κB signalling 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 (α) receptor adaptor protein 6 (TRAF6) in microglia. Our study suggests a key role for Bid in the regulation of TLR4-NF-κB pro-inflammatory signalling during mutant SOD1-induced disease pathology.Significance Statement: Recent work suggests that many pro-apoptotic proteins also function in other cell signalling pathways and may affect inflammatory responses. Inflammation is a hallmark of ALS disease models, and inflammation-associated markers in ALS patients are associated with more severe disease progression. Here we demonstrate that the pro-apoptotic Bcl-2 family protein Bid plays a crucial role in mutant SOD1-induced microglial activation, and delineate a novel signal transduction pathway activated by Bid involving K63-linked polyubiquitination of the E3 ubiquitin ligase tumor necrosis factor (α) receptor adaptor protein 6 (TRAF6) and subsequent NF-κB activation. ER -