Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.     

Host plants influence parasitism of forest caterpillars

Patterns of association between herbivores and host plants have been thought to reflect the quality of plants as food resources as influenced by plant nutrient composition, defences, and phenology. Host-plant-specific enemies, that is, the third trophic level, might also influence the distribution of herbivores across plant species. However, studies of the evolution of herbivore host range have generally not examined the third trophic level, leaving unclear the importance of this factor in the evolution of plant-insect herbivore interactions. Analysis of parasitoid rearings by the Canadian Forest Insect Survey shows that parasitism of particular Lepidoptera species is strongly host-plant-dependent, that the pattern of host-plant dependence varies among species of caterpillars, and that some parasitoid species are themselves specialized with respect to tree species. Host-plant-dependent parasitism suggests the possibility of top-down influence on host plant use. Differences in parasitism among particular caterpillar-host plant combinations could select for specialization of host plant ranges within caterpillar communities. Such specialization would ultimately promote the species diversification of Lepidoptera in temperate forests with respect to escape from enemies.     

Host specificity of Lepidoptera in tropical and temperate forests

For numerous taxa, species richness is much higher in tropical than in temperate zone habitats. A major challenge in community ecology and evolutionary biogeography is to reveal the mechanisms underlying these differences. For herbivorous insects, one such mechanism leading to an increased number of species in a given locale could be increased ecological specialization, resulting in a greater proportion of insect species occupying narrow niches within a community. We tested this hypothesis by comparing host specialization in larval Lepidoptera (moths and butterflies) at eight different New World forest sites ranging in latitude from 15 degrees S to 55 degrees N. Here we show that larval diets of tropical Lepidoptera are more specialized than those of their temperate forest counterparts: tropical species on average feed on fewer plant species, genera and families than do temperate caterpillars. This result holds true whether calculated per lepidopteran family or for a caterpillar assemblage as a whole. As a result, there is greater turnover in caterpillar species composition (greater beta diversity) between tree species in tropical faunas than in temperate faunas. We suggest that greater specialization in tropical faunas is the result of differences in trophic interactions; for example, there are more distinct plant secondary chemical profiles from one tree species to the next in tropical forests than in temperate forests as well as more diverse and chronic pressures from natural enemy communities.     

Localization and functionality of microsporidian iron-sulphur cluster assembly proteins

Microsporidia are highly specialized obligate intracellular parasites of other eukaryotes (including humans) that show extreme reduction at the molecular, cellular and biochemical level. Although microsporidia have long been considered as early branching eukaryotes that lack mitochondria, they have recently been shown to contain a tiny mitochondrial remnant called a mitosome. The function of the mitosome is unknown, because microsporidians lack the genes for canonical mitochondrial functions, such as aerobic respiration and haem biosynthesis. However, microsporidial genomes encode several components of the mitochondrial iron-sulphur (Fe-S) cluster assembly machinery. Here we provide experimental insights into the metabolic function and localization of these proteins. We cloned, functionally characterized and localized homologues of several central mitochondrial Fe-S cluster assembly components for the microsporidians Encephalitozoon cuniculi and Trachipleistophora hominis. Several microsporidial proteins can functionally replace their yeast counterparts in Fe-S protein biogenesis. In E. cuniculi, the iron (frataxin) and sulphur (cysteine desulphurase, Nfs1) donors and the scaffold protein (Isu1) co-localize with mitochondrial Hsp70 to the mitosome, consistent with it being the functional site for Fe-S cluster biosynthesis. In T. hominis, mitochondrial Hsp70 and the essential sulphur donor (Nfs1) are still in the mitosome, but surprisingly the main pools of Isu1 and frataxin are cytosolic, creating a conundrum of how these key components of Fe-S cluster biosynthesis coordinate their function. Together, our studies identify the essential biosynthetic process of Fe-S protein assembly as a key function of microsporidian mitosomes.