Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes.

The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a-GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations

Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.

Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2-/-Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2-/-Fancd2-/- HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging

Threatened and Endangered Subspecies with Vulnerable Ecological Traits Also Have High Susceptibility to Sea Level Rise and Habitat Fragmentation

<div><p>The presence of multiple interacting threats to biodiversity and the increasing rate of species extinction make it critical to prioritize management efforts on species and communities that maximize conservation success. We implemented a multi-step approach that coupled vulnerability assessments evaluating threats to Florida taxa such as climate change, sea-level rise, and habitat fragmentation with in-depth literature surveys of taxon-specific ecological traits. The vulnerability, adaptive capacity, and ecological traits of 12 threatened and endangered subspecies were compared to non-listed subspecies of the same parent species. Overall, the threatened and endangered subspecies showed high vulnerability and low adaptive capacity, in particular to sea level rise and habitat fragmentation. They also exhibited larger home ranges and greater dispersal limitation compared to non-endangered subspecies, which may inhibit their ability to track changing climate in fragmented landscapes. There was evidence for lower reproductive capacity in some of the threatened or endangered taxa, but not for most. Taxa located in the Florida Keys or in other low coastal areas were most vulnerable to sea level rise, and also showed low levels of adaptive capacity, indicating they may have a lower probability of conservation success. Our analysis of at-risk subspecies and closely related non-endangered subspecies demonstrates that ecological traits help to explain observed differences in vulnerability and adaptive capacity. This study points to the importance of assessing the relative contributions of multiple threats and evaluating conservation value at the species (or subspecies) level when resources are limited and several factors affect conservation success.</p></div