Design principles for inflammasome inhibition by pyrin-only-proteins

Inflammasomes are filamentous signaling platforms essential for host defense against various intracellular calamities such as pathogen invasion and genotoxic stresses. However, dysregulated inflammasomes cause an array of human diseases including autoinflammatory disorders and cancer. It was recently identified that endogenous pyrin-only-proteins (POPs) regulate inflammasomes by directly inhibiting their filament assembly. Here, by combining Rosetta in silico, in vitro, and in cellulo methods, we investigate the target specificity and inhibition mechanisms of POPs. We find here that POP1 is ineffective in directly inhibiting the central inflammasome adaptor ASC. Instead, POP1 acts as a decoy and targets the assembly of upstream receptor pyrin-domain (PYD) filaments such as those of AIM2, IFI16, NLRP3, and NLRP6. Moreover, not only does POP2 directly suppress the nucleation of ASC, but it can also inhibit the elongation of receptor filaments. In addition to inhibiting the elongation of AIM2 and NLRP6 filaments, POP3 potently suppresses the nucleation of ASC. Our Rosetta analyses and biochemical experiments consistently suggest that a combination of favorable and unfavorable interactions between POPs and PYDs is necessary for effective recognition and inhibition. Together, we reveal the intrinsic target redundancy of POPs and their inhibitory mechanisms

Adaptation and incipient sympatric speciation of Bacillus simplex under microclimatic contrast at “Evolution Canyons” I and II, Israel

The microevolutionary dynamics of prokaryotes in natural habitats, such as soil, is poorly understood in contrast to our increasing knowledge on their immense diversity. We performed microevolutionary analyses on 945 soil isolates of Bacillus simplex from “Evolution Canyons” I (Carmel, Israel) and II (Galilee, Israel). These canyons represent similar ecological replicates, separated by 40 km, with highly contrasting interslope abiotic and biotic conditions in each (within a distance of only 100–400 m). Strains representing genetic groups were identical in their 16S sequences, suggesting high genetic similarity and monophyletic origin. Parallel and nested phylogenetic structures correlated with ecological contrasts rather than geographical distance. Additionally, slope-specific populations differed substantially in their diversity. The levels of DNA repair (determined by UV sensitivity) and spontaneous mutation rate (resistance to rifampicin) relate to ecological stress and phylogeny. Altogether, the results suggest adaptive radiation at a microscale. We discuss the observed adaptive population structures in the context of incipient sympatric speciation in soil bacteria. We conclude that, despite different biology, prokaryotes, like sexually reproducing eukaryotes, may consist of true species and parallel ecological speciation in eukaryotes