IκB kinase ε (IKKε): a therapeutic target in inflammation and cancer

Abstract

The innate immune system forms our first line of defense against invading pathogens and relies for a major part on the activation of two transcription factors, NF-κB and IRF3. Signaling pathways that activate these transcription factors are intertwined at the level of the canonical IκB kinases (IKKα, IKKβ) and non-canonical IKK-related kinases (IKKε, TBK1). Recently, significant progress has been made in understanding the function and mechanism of action of IKKε in immune signaling. In addition, IKKε impacts on cell proliferation and transformation, and is thereby also classified as an oncogene. Studies with IKKε knockout mice have illustrated a key role for IKKε in inflammatory and metabolic diseases. In this review we will highlight the mechanisms by which IKKε impacts on signaling pathways involved in disease development and discuss its potential as a novel therapeutic target.

Graphical abstract

Fig. 1

Domain structure of the IKK family. The IKK family can be divided in two groups: the classical or canonical IKKs (IKKα and IKKβ) and the non-canonical IKKs (TBK1 and IKKɛ). In addition, two splice variants of IKKɛ (IKKɛ-sv1 and IKKɛ-sv2), respectively missing 25 and 13 amino acids at their C-terminal end, have been described. The following domains are depicted: kinase domain (KD), leucine zipper (LZ), helix-loop-helix (HLH), NEMO-binding domain (NBD), ubiquitin-like domain (ULD). Numbers indicate kinase-activating phosphorylation sites.

Fig. 2

IKKɛ mediated signaling to NF-κB and IRF3 in response to specific receptors. Non-canonical IKKs (IKKɛ and TBK1) can be activated by two signaling pathways: (1) IKKα/β mediated activation of IKKɛ/TBK1. Ligand binding to several receptors (TNF-R1, IL-1R, TLR4, RIG-I) initiates the recruitment of specific adaptor proteins (e.g. Mal, MyD88, TRAM, TRIF, MAVS), E3 ubiquitin ligases and kinases (not shown) to the receptor, eventually resulting in the activation of the canonical IKK (IKKα/IKKβ/NEMO) complex. This leads to the IKKβ-mediated phosphorylation and subsequent Lys48-linked polyubiquitination of IκBα, resulting in its proteasomal degradation and release of the p50–p65 NF-κB heterodimer, which then translocates to the nucleus. (2) IKKα/IKKβ-independent and TRAF3-dependent IKKɛ/TBK1 autoactivation. TRIF-dependent TLR3 and TLR4 signaling, as well as MAVS-dependent RIG-I signaling, induce IKKɛ/TBK1 autoactivation via TRAF3. This also requires the binding of IKKɛ/TBK1 to different scaffold proteins (TANK, NAP1, SINTBAD). IKKɛ/TBK1 then mediate different activities: (A) IKKɛ/TBK1 can phosphorylate NF-κB (p65), contributing to NF-κB dependent expression of specific genes. (B) IKKɛ/TBK1 can phosphorylate IRF3 (and IRF7; not shown), leading to its homodimerization and nuclear translocation. (C) IKKɛ/TBK1 can phosphorylate c-jun, leading to the release of the nuclear repressor complex (NCoR). (D) IKKɛ/TBK1 can phosphorylate their own scaffold proteins (TANK, NAP1 or SINTBAD), the function of which is still unclear. (E) IKKɛ/TBK1 is also able to phosphorylate the canonical IKKs, leading to their inactivation.

Fig. 3

Mechanisms contributing to the oncogenic potential of IKKɛ. Overexpression of IKKɛ in tumor cells induces cell survival, cell transformation and proliferation by different mechanisms involving IKKɛ mediated phosphorylation of specific substrates. IKKɛ can either directly or indirectly (via Akt phosphorylation and activation) phosphorylate NF-κB (p65), leading to increased NF-κB dependent gene expression. IKKɛ also phosphorylates and inactivates the tumor suppressor CYLD, preventing CYLD from deubiquitinating specific substrates in the NF-κB signaling pathway. In addition, phosphorylation of TRAF2 activates its E3 ubiquitin ligase activity. Both CYLD and TRAF2 phosphorylation thus increase ubiquitin-dependent NF-κB signaling. IKKɛ also directly phosphorylates STAT1, increasing its gene activating potential.