Biology subjects

Cuervo, A. M.

Publications and source records attributed to Cuervo, A. M..

5 recordsLinked to original sources

bioRxiv2018

The ULK1-FBXW5-SEC23B nexus controls autophagy

In response to nutrient deprivation, the cell needs to mobilize an extensive amount of membrane to form and grow the autophagosome, allowing the progression of autophagy. By providing membranes and a source for LC3 lipidation, COPII (Coat Protein Complex II) localizes to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and promotes autophagosome biogenesis. However, the molecular mechanisms that, in response to starvation, divert COPII from the secretory pathway to the autophagic pathway are largely unknown. Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting its degradation. Phosphorylated and stabilized SEC23B associates with SEC24A and SEC24B, but not SEC24C and SEC24D, and they re-localize to the ERGIC, promoting autophagic flux. Induction of autophagy and localization of both SEC23B and SEC24B to the ERGIC in response to nutrient deprivation are significantly reduced in SEC23B(S186A) knock-in cells. We propose that, in the presence of nutrients, FBXW5 limits COPII-mediated autophagosome biogenesis. Inhibition of this event by ULK1 ensures efficient execution of the autophagic cascade in response to nutrient starvation.

cell biology↗

bioRxiv2018

Tau Secretion and Propagation Is Regulated by p300/CBP via Autophagy-Lysosomal Pathway in Tauopathy

The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. Tau secretion from neurons is the first step in tau transmission, but little is known about the cellular mechanism. Here, we report that p300/CBP, the lysine acetyltransferase that acetylates tau and regulates its homeostasis and toxicity, serves as a key regulator of tau secretion by inhibiting the autophagy-lysosomal pathway (ALP). Increased p300/CBP activity was associated with impaired function of this pathway in a tau transgenic mouse model. p300/CBP hyperactivation increased tau secretion by blocking autophagic flux. Conversely, inhibiting p300/CBP genetically or pharmacologically promoted autophagic flux, and reduced tau accumulation, tau secretion, and tau propagation in fibril-induced tau spreading models in vitro and in vivo. Our findings show that p300/CBP-induced impairment in the ALP underlies excessive unconventional secretion and pathogenic spread of tau.

neuroscience↗

bioRxiv2018

Shallow evolutionary divergence between two Andean hummingbirds: Speciation with gene flow?

Ecological speciation can proceed despite genetic interchange when selection counteracts homogeneizing effects of migration. We tested predictions of this divergence-with-gene-flow model in Coeligena helianthea and C. bonapartei, two parapatric Andean hummigbirds with marked plumage divergence. We sequenced neutral markers (mtDNA and nuclear ultra conserved elements) to examine genetic structure and gene flow, and a candidate gene (MC1R) to assess its role underlying divergence in coloration. We also tested the prediction of Glogers rule that darker forms occur in more humid environments, and compared ecomorphological variables to assess adaptive mechanisms potentially promoting divergence. Genetic differentiation between species was very low and coalescent estimates of migration were consistent with divergence with gene flow. MC1R variation was unrelated to phenotypic differences. Species did not differ in macroclimatic niches but were distinct in ecomorphology. Although we reject adaptation to variation in humidity as the cause of divergence, we hypothesize that speciation likely occurred in the face of gene flow, driven by other ecological pressures or by sexual selection. Marked phenotypic divergence with no neutral genetic differentiation is remarkable for Neotropical birds, and makes C. helianthea and C. bonapartei an appropriate system in which to search for the genetic basis of species differences employing genomics.

evolutionary biology↗

bioRxiv2017

An extinct hummingbird species that never was: a cautionary tale about sampling issues in molecular phylogenetics

The Bogota Sunangel (Heliangelus zusii) was described based on a historical specimen lacking locality data as a striking-and potentially extinct- new species of hummingbird more than two decades ago. However, it was considered a dubious taxon by some researchers until a molecular study with strong species-level taxon sampling revealed its phylogenetic affinities and validated its status as a distinct species. We reanalysed existing mitochondrial DNA data together with a new data set sampling multiple populations of the Long-tailed Sylph (Aglaiocercus kingii), a species broadly distributed in the Andes of South America. In contrast to previous work, we found that H. zusii shares a haplotype with specimens of A. kingii from the Eastern Cordillera of Colombia, which is phylogenetically nested within a clade formed by populations of A. kingii from the Colombian Andes. These results suggest that H. zusii is not a distinct species, but is most likely the result of hybridization between a female A. kingii and a male of another hummingbird species. These findings highlight the importance of thorough taxonomic and geographic sampling when assessing the likelihood of hybrid origin of an organism, particularly in cases potentially involving wide-ranging species in areas where deep phylogeographic structure is likely.

evolutionary biology↗

bioRxiv2016

A positive association between population genetic differentiation and speciation rates in New World birds

Although an implicit assumption of speciation biology is that population differentiation is an important stage of evolutionary diversification, its true significance remains largely untested. If population differentiation within a species is related to its speciation rate over evolutionary time, the causes of differentiation could also be driving dynamics of organismal diversity across time and space. Alternatively, geographic variants might be short-lived entities with rates of formation that are unlinked to speciation rates, in which case the causes of differentiation would have only ephemeral impacts. Combining population genetics datasets including 17,746 individuals from 176 New World bird species with speciation rates estimated from phylogenetic data, we show that the population differentiation rates within species predict their speciation rates over long timescales. Although relatively little variance in speciation rate is explained by population differentiation rate, the relationship between the two is robust to diverse strategies of sampling and analyzing both population-level and species-level datasets. Population differentiation occurs at least three to five times faster than speciation, suggesting that most populations are ephemeral. Population differentiation and speciation rates are more tightly linked in tropical species than temperate species, consistent with a history of more stable diversification dynamics through time in the Tropics. Overall, our results suggest investigations into the processes responsible for population differentiation can reveal factors that contribute to broad-scale patterns of diversity.

evolutionary biology↗