Reactome | TBK1, IKBKE binds Met1-polyUb within the TNFR1 complex

TBK1, IKBKE binds Met1-polyUb within the TNFR1 complex

Stable Identifier

R-HSA-9817411

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, plasma membrane

ReviewStatus

5/5

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TBK1, IKBKE binds Met1-polyUb within the TNFR1 complex

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The catalytic activity of linear ubiquitin chain assembly complex (LUBAC) enables recruitment of TRAF-associated NF-κB activator (TANK) binding kinase 1 (TBK1) and inhibitor-kappa-B kinase (IKK) epsilon (IKKε or IKBKE) to the TNFR1 signaling complex, also known as complex-I (Lafont E et al. 2018; Xu D et al. 2018). LUBAC, composed of the HOIP, HOIL-1L, and SHARPIN subunits, generates linear Met1-linked polyubiquitin chains. HOIP deficiency strongly diminished recruitment of TBK1 or IKBKE to the complex-I in human epithelial cervical carcinoma HeLa cells and lung carcinoma A549 cells (Lafont E et al. 2018). Western blot analysis revealed that TBK1 and IKBKE are recruited to and strongly phosphorylated within the TNFR1 complex in various TNFα-stimulated human cell lines including A549, keratinocyte HaCaT, monocytic U937 and THP-1 cells (Lafont E et al. 2018). Similarly, TBK1 was found to associate with components of the complex-I in the LUBAC-dependent manner in mouse cells (Xu D et al. 2018). IKBKE, but not TBK1, was detected within the TNFR1 complex in human telomerase reverse transcriptase (TERT)-immortalized dermal fibroblasts derived from patients with TBK1 deficiency as a result of loss-of-function mutation at W619* (Taft J et al. 2021). The enzymatic activity of TBK1/IKBKE is initiated by phosphorylation at S172 located in the T loop of the TBK1 and IKKε kinase domains (Shimada T et al. 1999; Kishore N et al. 2002; Gu L et al. 2013). Activated TBK1 and IKBKE are known to trigger phosphorylation of interferon regulatory factor 3 (IRF3) and IRF7 and subsequent expression of type I interferons (IFNs; IFN-α/β) downstream of pattern recognition receptors, such as Toll-like receptors 3 and 4 (TLR3, TLR4), cGAS/STING and RIG-I-like receptors (Fitzgerald KA et al. 2003; Fang R et al. 2017). While TBK1 or IKBKE showed limited effect on TNFα-induced gene expression in human A549 and mouse embryonic fibroblasts (MEF) (Lafont E et al. 2018), both kinases prevented TNFα-induced cell death by suppressing RIPK1 activation in human and mouse cells (Lafont E et al. 2018; Xu D et al. 2018; Taft J et al. 2021). TBK1 and/or IKBKE directly phosphorylate RIPK1 within the TNFR1 signaling complex to prevent RIPK1 kinase-dependent cell death downstream of TNFR1 (Lafont E et al. 2018; Xu D et al. 2018). TBK1 or IKBKE deficiency enhanced TNF-induced autophosphorylation of RIPK1, association of RIPK3 with caspase-8:FADD and phosphorylation of MLKL in human A549 and HeLa cells (Lafont E et al. 2018). Similar findings were reported for mouse cells (Lafont E et al. 2018; Xu D et al. 2018). In vivo studies showed that the embryonic lethality of Tbk1−/− mice was caused by TNFα-stimulated hyperactivation of RIPK1 kinase activity (Xu D et al. 2018). Furthermore, chronic systemic autoinflammation in patients carrying homozygous loss-of-function mutations in TBK1 (W619*, R440* and Y212D) is associated with the enhanced TNFα-induced RIPK1-dependent cell death (Taft J et al. 2021). In addition, TBK1-mediated phosphorylation of CYLD may also control the TNFR1 signaling pathway by regulating the ubiquitination status of RIPK1 (Xu X et al. 2020; Taft J et al. 2021). These data suggest that TBK1 and IKBKE downregulate RIPK1 auto-phosphorylation within the complex-I, thereby preventing TNFα- induced RIPK1-kinase-activity-dependent cell death.

This Reactome event describes TBK1/IKBKE recruitment to and activation within the TNFR1 signaling complex.

Literature References

PubMed ID	Title	Journal	Year
30420664	TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation Lafont, E, Draber, P, Rieser, E, Reichert, M, Kupka, S, de Miguel, D, Draberova, H, von Mässenhausen, A, Bhamra, A, Henderson, S, Wojdyla, K, Chalk, A, Surinova, S, Linkermann, A, Walczak, H	Nat. Cell Biol.	2018
30146158	TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging Xu, D, Jin, T, Zhu, H, Chen, H, Ofengeim, D, Zou, C, Mifflin, L, Pan, L, Amin, P, Li, W, Shan, B, Naito, MG, Meng, H, Li, Y, Pan, H, Aron, L, Adiconis, X, Levin, JZ, Yankner, BA, Yuan, J	Cell	2018
34363755	Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death Taft, J, Markson, M, Legarda, D, Patel, R, Chan, M, Malle, L, Richardson, A, Gruber, C, Martín-Fernández, M, Mancini, GMS, van Laar, JAM, van Pelt, P, Buta, S, Wokke, BHA, Sabli, IKD, Sancho-Shimizu, V, Chavan, PP, Schnappauf, O, Khubchandani, R, Cüceoğlu, MK, Özen, S, Kastner, DL, Ting, AT, Aksentijevich, I, Hollink, IHIM, Bogunovic, D	Cell	2021