The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH2 domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.

Nuclear pore proteins (Nups) prominently are among the few genes linked to speciation from hybrid incompatibility in Drosophila. Moreover, neuronal wiring underlying the female post-mating response induced by male-derived sex-peptide requires channel Nup54 functionality. A hot spot for rapid evolution in the promoter of Nup54 suggests a critical role for regulatory elements at the onset of speciation. Systematic analysis of Nup coding and promoter regions using Drosophila phylogenomics reveals that polymorphisms between closely related Drosophila species in Nup open reading frames do not generally drive rapid evolution. Analysis of Nup gene upstream regions indicated a bias for changes compared to those downstream. Consistent with findings for Nup54, the other channel Nups 58 and 62 promotor regions are also hotpots for rapid accumulation of insertions/deletions (indels). Further examination of upstream regions of all Nup genes reveals that core nuclear pore complex gene promoters accumulate indels at a faster rate. Since changes in promoters have dominant effects, these results indicate a novel mechanism of evolution driven through accumulation of indels in core Nup gene promoters. Compensation of such deleterious changes could lead to altered neuronal wiring, rapid fixation of adaptive traits and subsequently the rise of new species. Hence, the nuclear pore complex may act as a nexus for species-specific changes via nucleo-cytoplasmic transport regulated gene expression.

Nuclear pore proteins (Nups) prominently are among the few genes linked to speciation from hybrid incompatibility in Drosophila. These studies have focused on coding sequence evolution of Nup96 and Nup160 and shown evidence of positive selection driving nucleoporin evolution. Intriguingly, channel Nup54 functionality is required for neuronal wiring underlying the female post-mating response induced by male-derived sex-peptide. A region of rapid evolution in the core promoter of Nup54 suggests a critical role for general transcriptional regulatory elements at the onset of speciation, but whether this is a general feature of Nup genes has not been determined. Consistent with findings for Nup54, additional channel Nup58 and Nup62 promoters also rapidly accumulate insertions/deletions (indels). Comprehensive examination of Nup upstream regions reveals that core Nup complex gene promoters accumulate indels rapidly. Since changes in promoters can drive changes in expression, these results indicate an evolutionary mechanism driven by indel accumulation in core Nup promoters. Compensation of such gene expression changes could lead to altered neuronal wiring, rapid fixation of traits caused by promoter changes and subsequently the rise of new species. Hence, the nuclear pore complex may act as a nexus for species-specific changes via nucleo-cytoplasmic transport regulated gene expression.