The emerging role of human TBK1 in virus-induced autophagy
Authors: Liyana, Ahmad; Vanessa, Sancho-Shimizu
Recent studies have suggested a role for TBK1 in mediating inflammation through macroautophagy/autophagy. While its function in inducing interferon production in response to viral infection has been extensively studied, its role in antiviral autophagy is only beginning to be appreciated. Herein we discuss the role of this multifunctional protein in both antiviral IFN production and in cytoprotective autophagy during HSV-1 infection. Lastly, we highlight the potential implication of TBK1 in the management of inflammation through autophagy, particularly within the central nervous system.
TBK1 and IKK epsilon prevent TNF-induced cell death by RIPK1 phosphorylation
NATURE CELL BIOLOGY
Authors: Lafont, Elodie; Draber, Peter; Rieser, Eva; Reichert, Matthias; Kupka, Sebastian; de Miguel, Diego; Draberova, Helena; von Maessenhausen, Anne; Bhamra, Amandeep; Henderson, Stephen; Wojdyla, Katarzyna; Chalk, Avigayil; Surinova, Silvia; Linkermann, Andreas; Walczak, Henning
The linear-ubiquitin chain assembly complex (LUBAC) modulates signalling via various immune receptors. In tumour necrosis factor (TNF) signalling, linear (also known as M1) ubiquitin enables full gene activation and prevents cell death. However, the mechanisms underlying cell death prevention remain ill-defined. Here, we show that LUBAC activity enables TBK1 and IKK epsilon recruitment to and activation at the TNF receptor 1 signalling complex (TNFR1-SC). While exerting only limited effects on TNF-induced gene activation, TBK1 and IKKe are essential to prevent TNF-induced cell death. Mechanistically, TBK1 and IKK epsilon phosphorylate the kinase RIPK1 in the TNFR1-SC, thereby preventing RIPK1-dependent cell death. This activity is essential in vivo, as it prevents TNF-induced lethal shock. Strikingly, NEMO (also known as IKK gamma), which mostly, but not exclusively, binds the TNFR1-SC via M1 ubiquitin, mediates the recruitment of the adaptors TANK and NAP1 (also known as AZI2). TANK is constitutively associated with both TBK1 and IKKe, while NAP1 is associated with TBK1. We discovered a previously unrecognized cell death checkpoint that is mediated by TBK1 and IKK epsilon, and uncovered an essential survival function for NEMO, whereby it enables the recruitment and activation of these non-canonical IKKs to prevent TNF-induced cell death.