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Bid Promotes K63-Linked Polyubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) and Sensitizes to Mutant SOD1-Induced Proinflammatory Signaling in Microglia.

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Version 1 2019-11-22, 17:07
journal contribution
posted on 2019-11-22, 17:07 authored by Sinéad Kinsella, Hans-Georg König, Jochen HM Prehn

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.

Funding

This work was supported by the BioAnalysis and Therapeutics PhD scholars program under the Programme for Research in Third Level Institutions (PRTLI) Cycle 5 and funding from the Science Foundation Ireland (08/INV.1/B1949). The PRTLI is co-funded through the European Regional Development Fund, part of the European Union Structural Funds Programme 2007–2013. We thank Mathew King for the generation of the plasmids encoding the SOD1G93A-CFP fusion protein, Ina Woods and Shona Pfeiffer for proficient technical assistance in animal breeding, Caroline Jefferies for some valuable advice and for donating the Ubiquitin encoding plasmid, and Manuela Salvucci for assistance with statistical analyses.

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This article is also available at http://eneuro.org/content/3/2

Published Citation

Kinsella S, König HG, Prehn HJM. 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. 2016 May 12;3(2). pii: ENEURO.))99-15.2016.

Publication Date

2016-03-01

Publisher

Society of Neuroscience

PubMed ID

27257617