NF-kappaB-inducing kinase in cancer.

Dysregulation of the alternative NF-κB signaling has severe developmental consequences that can ultimately lead to oncogenesis. Pivotal for the activation of the alternative NF-κB pathway is the stabilization of the NF-κB-inducing kinase (NIK). The aim of this review is to focus on the emerging role of NIK in cancer. The documented subversion of NIK in cancers highlights NIK as a possible therapeutic target. Recent studies show that the alterations of NIK or the components of its regulatory complex are manifold including regulation on the transcript level, copy number changes, mutations as well as protein modifications. High NIK activity is associated with different human malignancies and has adverse effects on tumor patient survival. We discuss here research focusing on deciphering the contribution of NIK towards cancer development and progression. We also report that it is possible to engineer inhibitors with high specificity for NIK and describe developments in this area.

Pathogen-induced ubiquitin-editing enzyme A20 bifunctionally shuts off NF-κB and caspase-8-dependent apoptotic cell death.

The human pathogen Helicobacter pylori infects more than half of the world's population and is a paradigm for persistent yet asymptomatic infection but increases the risk for chronic gastritis and gastric adenocarcinoma. For successful colonization, H. pylori needs to subvert the host cell death response, which serves to confine pathogen infection by killing infected cells and preventing malignant transformation. Infection of gastric epithelial cells by H. pylori provokes direct and fast activation of the proinflammatory and survival factor NF-κB, which regulates target genes, such as CXCL8, BIRC3 and TNFAIP3. However, it is not known how H. pylori exploits NF-κB activation and suppresses the inflammatory response and host apoptotic cell death, in order to avert the innate immune response and avoid cell loss, and thereby enhance colonization to establish long-term infection. Here we assign for the first time that H. pylori and also Campylobacter jejuni-induced ubiquitin-editing enzyme A20 bifunctionally terminates NF-κB activity and negatively regulates apoptotic cell death. Mechanistically, we show that the deubiquitinylase activity of A20 counteracts cullin3-mediated K63-linked ubiquitinylation of procaspase-8, therefore restricting the activity of caspase-8. Interestingly, another inducible NF-κB target gene, the scaffold protein p62, ameliorates the interaction of A20 with procaspase-8. In conclusion, pathogen-induced de novo synthesis of A20 regulates the shut-off of the survival factor NF-κB but, on the other hand, also impedes caspase-8-dependent apoptotic cell death so as to promote the persistence of pathogens.