Mireille Delhase

The IκB Kinase Complex (IKK) Contains Two Kinase Subunits, IKKα and IKKβ, Necessary for IκB Phosphorylation and NF-κB Activation

Recently we purified a 900 kDa cytokine-responsive IkappaB kinase complex (IKK) and molecularly cloned one of its subunits, IKKalpha, a serine kinase. We now describe the molecular cloning and characterization of IKKbeta, a second subunit of the IKK complex. IKKbeta is 50% identical to IKKalpha and like it contains a kinase domain, a leucine zipper, and a helix-loop-helix. Although IKKalpha and IKKbeta can undergo homotypic interaction, they also interact with each other and the functional IKK complex contains both subunits. The catalytic activities of both IKKalpha and IKKbeta make essential contributions to IkappaB phosphorylation and NF-kappaB activation. While the interactions between IKKalpha and IKKbeta may be mediated through their leucine zipper motifs, their helix-loop-helix motifs may be involved in interactions with essential regulatory subunits.

The Lymphotoxin-β Receptor Induces Different Patterns of Gene Expression via Two NF-κB Pathways

The lymphotoxin-beta receptor (LTbetaR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kappaB. In addition to activation of the classical NF-kappaB, ligation of this receptor induces the processing of the cytosolic NF-kappaB2/p100 precursor to yield the mature p52 subunit, followed by translocation of p52 to the nucleus. This activation of NF-kappaB2 requires NIK and IKKalpha, while NEMO/IKKgamma is dispensable for p100 processing. IKKbeta-dependent activation of canonical NF-kappaB is required for the expression but not processing of p100 and for the expression of proinflammatory molecules including VCAM-1, MIP-1beta, and MIP-2 in response to LTbetaR ligation. In contrast, IKKalpha controls the induction by LTbetaR ligation of chemokines and cytokines involved in lymphoid organogenesis, including SLC, BLC, ELC, SDF1, and BAFF.

CK2 Is a C-Terminal IκB Kinase Responsible for NF-κB Activation during the UV Response

Abstract NF-κB is activated in response to proinflammatory stimuli, infections, and physical stress. While activation of NF-κB by many stimuli depends on the IκB kinase (IKK) complex, which phosphorylates IκBs at N-terminal sites, the mechanism of NF-κB activation by ultraviolet (UV) radiation remained enigmatic, as it is IKK independent. We now show that UV-induced NF-κB activation depends on phosphorylation of IκBα at a cluster of C-terminal sites that are recognized by CK2 (formerly casein kinase II). Furthermore, CK2 activity toward IκB is UV inducible through a mechanism that depends on activation of p38 MAP kinase. Inhibition of this pathway prevents UV-induced IκBα degradation and increases UV-induced cell death. Thus, the p38-CK2-NF-κB axis is an important component of the mammalian UV response.

NAK is an IkappaB kinase-activating kinase.

Phosphorylation of IκB by the IκB kinase (IKK) complex is a critical step leading to IκB degradation and activation of transcription factor NF-κB. The IKK complex contains two catalytic subunits, IKKα and IKKβ, the latter being indispensable for NF-κB activation by pro-inflammatory cytokines. Although IKK is activated by phosphorylation of the IKKβ activation loop, the physiological IKK kinases that mediate responses to extracellular stimuli remain obscure. Here we describe an IKK-related kinase, named NAK (NF-κB-activating kinase), that can activate IKK through direct phosphorylation. NAK induces IκB degradation and NF-κB activity through IKKβ. Endogenous NAK is activated by phorbol ester tumour promoters and growth factors, whereas catalytically inactive NAK specifically inhibits activation of NF-κB by protein kinase C-ε (PKCε). Thus, NAK is an IKK kinase that may mediate IKK and NF-κB activation in response to growth factors that stimulate PKCε activity.

Signalling pathways: Kinase regulation in inflammatory response

The transcription factor NF-κB is a pivotal regulator of innate immune responses, whose activity is rapidly induced by proinflammatory stimuli, most notably the tumour-necrosis factor TNFα and interleukin-1, viruses, and components of bacterial cell walls. In addition, NF-κB protects cells from the induction of programmed cell death by pro-apoptotic stimuli such as TNFα (refs 2, 3). Another important anti-apoptotic signal-transducing protein is the protein kinase Akt (also known as protein kinase B), whose activity is strongly stimulated by growth factors. Ozes et al. have suggested that Akt is involved in the TNFα-mediated activation of NF-κB, implying that some of the anti-apoptotic activity of Akt may be mediated through NF-κB. However, we have failed to detect any involvement of Akt in the signalling pathway through which TNFα leads to NF-κB activation.

The Cytokine Odyssey 2001, a joint meeting of the Society of Leukocyte Biology and the International Cytokine Society

The Cytokine Odyssey 2001 was held at the Outrigger Wailea Resort in Maui, Hawaii, USA. The meeting, jointly sponsored by the International Cytokine Society (ICS, 9th Annual Meeting) and the Society of Leukocyte Biology (SLB, 35th Annual Meeting), was organised by Carl Ware (Chair) from the La Jolla Institute for Allergy and Immunology (La Jolla, USA) and Thomas Hamilton (Co-Chair) from the Cleveland Clinic Foundation (Cleveland, USA). This international conference was designed to bring together leading investigators in molecular and cellular biology, physiology and genetics, interested in cytokines and cells of the immune system. This forum was aimed to assess the impact of this expanding science on new approaches to disease intervention [1].