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Loss of the interferon-γ-inducible regulatory immunity-related GTPase (IRG), Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient mice to infection
Full text linkThe interferon-γ (IFN-γ)-inducible immunity-related GTPase (IRG), Irgm1, plays an essential role in restraining activation of the IRG pathogen resistance system. However, the loss of Irgm1 in mice also causes a dramatic but unexplained susceptibility phenotype upon infection with a variety of pathogens, including many not normally controlled by the IRG system. This phenotype is associated with lymphopenia, hemopoietic collapse, and death of the mouse.Deutscher Akademischer Austausch Dienst (DAAD); International Graduate School in Development Health
and Disease (IGS-DHD); Deutsche For-schungsgemeinschaft (SFBs 635, 670, 680); Max-Planck-Gesellschaft (Max Planck Fellowship)
The interplay between neuronal activity and actin dynamics mimic the setting of an LTD synaptic tag
Full text linkPersistent forms of plasticity, such as long-term depression (LTD), are dependent on the interplay between activity-dependent synaptic tags and the capture of plasticity-related proteins. We propose that the synaptic tag represents a structural alteration that turns synapses permissive to change. We found that modulation of actin dynamics has different roles in the induction and maintenance of LTD. Inhibition of either actin depolymerisation or polymerization blocks LTD induction whereas only the inhibition of actin depolymerisation blocks LTD maintenance. Interestingly, we found that actin depolymerisation and CaMKII activation are involved in LTD synaptic-tagging and capture. Moreover, inhibition of actin polymerisation mimics the setting of a synaptic tag, in an activity-dependent manner, allowing the expression of LTD in non-stimulated synapses. Suspending synaptic activation also restricts the time window of synaptic capture, which can be restored by inhibiting actin polymerization. Our results support our hypothesis that modulation of the actin cytoskeleton provides an input-specific signal for synaptic protein capture.Fundação para a Ciência e a Tecnologia grants: (IF/01359/2014; PTDC/NEO-SCC/3023/14 grants, IF/01359/2014); Instituto Gulbenkian de Ciência; Fundação Calouste Gulbenkian; Max-Planck Institute of Neurobiology
Transcriptomic comparison between two Vitis vinifera L. varieties (Trincadeira and Touriga Nacional) in abiotic stress conditions
Full text linkPredicted climate changes announce an increase of extreme environmental conditions including drought and excessive heat and light in classical viticultural regions. Thus, understanding how grapevine responds to these conditions and how different genotypes can adapt, is crucial for informed decisions on accurate viticultural actions. Global transcriptome analyses are useful for this purpose as the response to these abiotic stresses involves the interplay of complex and diverse cascades of physiological, cellular and molecular events. The main goal of the present work was to evaluate the response to diverse imposed abiotic stresses at the transcriptome level and to compare the response of two grapevine varieties with contrasting physiological trends, Trincadeira (TR) and Touriga Nacional (TN).Fundação para a Ciência e Tecnologia grant: (SFRH/BD/110274/2015)
Robust gap repair in the contractile ring ensures timely completion of cytokinesis
Full text linkCytokinesis in animal cells requires the constriction of an actomyosin contractile ring, whose architecture and mechanism remain poorly understood. We use laser microsurgery to explore the biophysical properties of constricting rings in Caenorhabditis elegans embryos. Laser cutting causes rings to snap open. However, instead of disintegrating, ring topology recovers and constriction proceeds. In response to severing, a finite gap forms and is repaired by recruitment of new material in an actin polymerization-dependent manner. An open ring is able to constrict, and rings repair from successive cuts. After gap repair, an increase in constriction velocity allows cytokinesis to complete at the same time as controls. Our analysis demonstrates that tension in the ring increases while net cortical tension at the site of ingression decreases throughout constriction and suggests that cytokinesis is accomplished by contractile modules that assemble and contract autonomously, enabling local repair of the actomyosin network. Consequently, cytokinesis is a highly robust process impervious to discontinuities in contractile ring structure.European Research Council grant: (640553); Fundo Europeu de Desenvolvimento Regional (FEDER) funds: (Operational Competitiveness Program - COMPETE); Fundação para a Ciência e a Tecnologia grant:(NORTE-07-0124-FEDER-000003); Fundação Luso-Americana para o Desenvolvimento (Life Science 2020); Louis-Jeantet Young Investigator Award; European Social Fund (Programa Operacional Temático Potencial Type 4.2); Programa Operacional Regional do Norte (Quadro de Referência Estratégico Nacional - FEDER).info:eu-repo/semantics/publishedVersio
Influenza A virus ribonucleoproteins modulate host recycling by competing with Rab11 effectors
Full text linkInfluenza A virus assembly is an unclear process, whereby individual virion components form an infectious particle. The segmented nature of the influenza A genome imposes a problem to assembly because it requires packaging of eight distinct RNA particles (vRNPs). It also allows genome mixing from distinct parental strains, events associated with influenza pandemic outbreaks. It is important to public health to understand how segmented genomes assemble, a process that is dependent on the transport of components to assembly sites. Previously, it has been shown that vRNPs are carried by recycling endosome vesicles, resulting in a change of Rab11 distribution. Here, we describe that vRNP binding to recycling endosomes impairs recycling endosome function, by competing for Rab11 binding with family-interacting proteins, and that there is a causal relationship between Rab11 ability to recruit family-interacting proteins and Rab11 redistribution. This competition reduces recycling sorting at an unclear step, resulting in clustering of single- and double-membraned vesicles. These morphological changes in Rab11 membranes are indicative of alterations in protein and lipid homeostasis during infection. Vesicular clustering creates hotspots of the vRNPs that need to interact to form an infectious particle.Fundação para a Ciência e Tecnologia grants: (PTDC/IMI-MIC/1142/2012, SFRH/BPD/94204/2013, SFRH/BPD/62982/2009, IF/00899/2013); Fundação Calouste Gulbenkian; Instituto Gulbenkian de Ciência
Hoxb6 can interfere with somitogenesis in the posterior embryo through a mechanism independent of its rib-promoting activity
Full text linkFormation of the vertebrate axial skeleton requires coordinated Hox gene activity. Hox group 6 genes are involved in the formation of the thoracic area owing to their unique rib-promoting properties. Here we show that the linker region (LR) connecting the homeodomain and the hexapeptide is essential for Hoxb6 rib-promoting activity in mice. The LR-defective Hoxb6 protein was still able to bind a target enhancer together with Pax3, producing a dominant-negative effect, indicating that the LR brings additional regulatory factors to target DNA elements. We also found an unexpected association between Hoxb6 and segmentation in the paraxial mesoderm. In particular, Hoxb6 can disturb somitogenesis and anterior-posterior somite patterning by dysregulation of Lfng expression. Interestingly, this interaction occurred differently in thoracic versus more caudal embryonic areas, indicating functional differences in somitogenesis before and after the trunk-to-tail transition. Our results suggest the requirement of precisely regulated Hoxb6 expression for proper segmentation at tailbud stages.Fundação para a Ciência e a Tecnologia grant: (PTDC/SAU-BID/110640/2009); FCT postdoctoral fellowship: (SFRH/BPD/89500/2012)
Novel insights into mitotic chromosome condensation
Full text linkThe fidelity of mitosis is essential for life, and successful completion of this process relies on drastic changes in chromosome organization at the onset of nuclear division. The mechanisms that govern chromosome compaction at every cell division cycle are still far from full comprehension, yet recent studies provide novel insights into this problem, challenging classical views on mitotic chromosome assembly. Here, we briefly introduce various models for chromosome assembly and known factors involved in the condensation process (e.g. condensin complexes and topoisomerase II). We will then focus on a few selected studies that have recently brought novel insights into the mysterious way chromosomes are condensed during nuclear division.The author(s) declared that no grants were involved in supporting this work
Macrophage adaptation leads to parallel evolution of genetically diverseEscherichia colismall-colony variants with increased fitness in vivo and antibiotic collateral sensitivity
Full text linkSmall-colony variants (SCVs) are commonly observed in evolution experiments and clinical isolates, being associated with antibiotic resistance and persistent infections. We recently observed the repeated emergence of Escherichia coli SCVs during adaptation to the interaction with macrophages. To identify the genetic targets underlying the emergence of this clinically relevant morphotype, we performed whole-genome sequencing of independently evolved SCV clones. We uncovered novel mutational targets, not previously associated with SCVs (e.g. cydA, pepP) and observed widespread functional parallelism. All SCV clones had mutations in genes related to the electron-transport chain. As SCVs emerged during adaptation to macrophages, and often show increased antibiotic resistance, we measured SCV fitness inside macrophages and measured their antibiotic resistance profiles. SCVs had a fitness advantage inside macrophages and showed increased aminoglycoside resistance in vitro, but had collateral sensitivity to other antibiotics (e.g. tetracycline). Importantly, we observed similar results in vivo. SCVs had a fitness advantage upon colonization of the mouse gut, which could be tuned by antibiotic treatment: kanamycin (aminoglycoside) increased SCV fitness, but tetracycline strongly reduced it. Our results highlight the power of using experimental evolution as the basis for identifying the causes and consequences of adaptation during host-microbe interactions.European Research Council under the European Community’ Seventh Framework Programme grant:(FP7/2007-2013); German Science Foundation grants: (G-410861, SFB-680); EMMA; InfrafrontierI3
Clustering of Rab11 vesicles in influenza A virus infected cells creates hotspots containing the 8 viral ribonucleoproteins
Full text linkInfluenza A virus is an important human pathogen causative of yearly epidemics and occasional pandemics. The ability to replicate within the host cell is a determinant of virulence, amplifying viral numbers for host-to-host transmission. This process requires multiple rounds of entering permissive cells, replication, and virion assembly at the plasma membrane, the site of viral budding and release. The assembly of influenza A virus involves packaging of several viral (and host) proteins and of a segmented genome, composed of 8 distinct RNAs in the form of viral ribonucleoproteins (vRNPs). The selective assembly of the 8-segment core remains one of the most interesting unresolved problems in virology. The recycling endosome regulatory GTPase Rab11 was shown to contribute to the process, by transporting vRNPs to the periphery, giving rise to enlarged cytosolic puncta rich in Rab11 and the 8 vRNPs. We recently reported that vRNP hotspots were formed of clustered vesicles harbouring protruding electron-dense structures that resembled vRNPs. Mechanistically, vRNP hotspots were formed as vRNPs outcompeted the cognate effectors of Rab11, the Rab11-Family-Interacting-Proteins (FIPs) for binding, and as a consequence impair recycling sorting at an unknown step. Here, we speculate on the impact that such impairment might have in host immunity, membrane architecture and viral assembly.Fundação para a Ciência e a Tecnologia grant: (IF/00899/2013)
Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
Full text linkIn the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers.National Institute of Neurological Disorders and Stroke grant: (1R01NS066936); March of Dimes Foundation grant: (#1-FY12-455).info:eu-repo/semantics/publishedVersio