Crosstalk between the NF-kappaB activating IKK-complex and the CSN signalosome.

A great variety of signalling pathways regulating inflammation, cell development and cell survival require NF-kappaB transcription factors, which are normally inactive due to binding to inhibitors, such as IkappaBalpha. The canonical activation pathway of NF-kappaB is initiated by phosphorylation of the inhibitor by an IkappaB kinase (IKK) complex triggering ubiquitination of IkappaB molecules by SCF-type E3-ligase complexes and rapid degradation by 26S-proteasomes. The ubiquitination machinery is regulated by the COP9 signalosome (CSN). We show that IkappaB kinases interact with the CSN-complex, as well as the SCF-ubiquitination machinery, providing an explanation for the rapid signalling-induced ubiquitination and degradation of IkappaBalpha. Furthermore, we reveal that IKK's phosphorylate not only IkappaBalpha, but also the CSN-subunit Csn5/JAB1 (c-Jun activation domain binding protein-1) and that IKK2 influences ubiquitination of Csn5/JAB1. Our observations imply that the CSN complex acts as an inhibitor of constitutive NF-kappaB activity in non-activated cells. Knock-down of Csn5/JAB1 clearly enhanced basal NF-kappaB activity and improved cell survival under stress. The inhibitory effect of Csn5/JAB1 requires a functional MPN(+) metalloprotease domain, which is responsible for cleaving ubiquitin-like Nedd8-modifications. Upon activation of cells with tumour necrosis factor-alpha, the CSN complex dissociates from IKK's allowing full and rapid activation of the NF-kappaB pathway by the concerted action of interacting protein complexes.

Contrasting patterns of natural variation in global Drosophila melanogaster populations.

Despite the popularity of Drosophila melanogaster in functional and evolutionary genetics, the global pattern of natural variation has not yet been comprehensively described in this species. For the first time, we report a combined survey using neutral microsatellites and mitochondrial sequence variation jointly. Thirty-five populations originating from five continents were compared. In agreement with previous microsatellite studies, sub-Saharan African populations were the most variable ones. Consistent with previous reports of a single 'out of Africa' habitat expansion, we found that non-African populations contained a subset of the African alleles. The pattern of variation detected for the mitochondrial sequences differed substantially. The most divergent haplotypes were detected in the Mediterranean region while Africa harboured most haplotypes, which were all closely related. In the light of the well-established African origin of D. melanogaster, our results cast severe doubts about the suitability of mtDNA for biogeographic inference in this model organism.

Highly structured Asian Drosophila melanogaster populations: a new tool for hitchhiking mapping?

Mark-recapture experiments showed that D. melanogaster has high dispersal capabilities. Consistent with a highly migratory species, only very low levels of differentiation were described for D. melanogaster populations from the same continent. We reinvestigated the population structure in D. melanogaster using 49 polymorphic markers in 23 natural populations. While European and American D. melanogaster populations showed very low differentiation, Asian D. melanogaster populations were highly structured. Despite the high differentiation of Asian flies, we confirm that all non-African populations are derived from a single colonization event. We propose that the availability of D. melanogaster populations with high and low population structure provides a novel tool for the identification of ecologically important adaptations by hitchhiking mapping.