The erythrocyte membrane properties of beta thalassaemia heterozygotes and their consequences for Plasmodium falciparum invasion

Malaria parasites such as Plasmodium falciparum have exerted formidable selective pressures on the human genome. Of the human genetic variants associated with malaria protection, beta thalassaemia (a haemoglobinopathy) was the earliest to be associated with malaria prevalence. However, the malaria protective properties of beta thalassaemic erythrocytes remain unclear. Here we studied the mechanics and surface protein expression of beta thalassaemia heterozygous erythrocytes, measured their susceptibility to P. falciparum invasion, and calculated the energy required for merozoites to invade them. We found invasion-relevant differences in beta thalassaemic cells versus matched controls, specifically: elevated membrane tension, reduced bending modulus, and higher levels of expression of the major invasion receptor basigin. However, these differences acted in opposition to each other with respect to their likely impact on invasion, and overall we did not observe beta thalassaemic cells to have lower P. falciparum invasion efficiency for any of the strains tested.

Membrane tension propagation couples axon growth and collateral branching

Neuronal axons must navigate a mechanically heterogeneous environment to reach their targets, but the biophysical mechanisms coupling mechanosensation, growth, and branching are not fully understood. Here, we show that local changes in membrane tension propagate along axons at approximately 20 μm/s, more than 1000-fold faster than in other non-motile cells. This rapid and long-range mechanical signaling mediates bidirectional competition between axonal branch initiation and growth cone extension. Our data suggest a mechanism by which mechanical cues at one part of a growing axon can affect growth dynamics remotely.

Caveolae promote successful abscission by controlling intercellular bridge tension during cytokinesis

During cytokinesis, the intercellular bridge (ICB) connecting the daughter cells experiences pulling forces, which delay abscission by preventing the assembly of the ESCRT scission machinery. Abscission is thus triggered by tension release, but how ICB tension is controlled is unknown. Here, we report that caveolae, which are known to control membrane tension upon mechanical stress in interphase cells, are located at the midbody, at the abscission site and at the ICB/cell interface in dividing cells. Functionally, the loss of caveolae delays ESCRT-III recruitment during cytokinesis and impairs abscission. This is the consequence of a 2-fold increase of ICB tension measured by laser ablation, associated with a local increase in myosin II activity at the ICB/cell interface. We thus propose that caveolae buffer membrane tension and limit contractibility at the ICB to promote ESCRT-III assembly and cytokinetic abscission. Altogether, this work reveals an unexpected connection between caveolae and the ESCRT machinery and the first role of caveolae in cell division.

Curcumin activation of a bacterial mechanosensitive channel underlies its membrane permeability and adjuvant properties

Curcumin, a natural compound isolated from the rhizome of turmeric, has been shown to have antibacterial properties. It has several physiological effects on bacteria including an apoptosis-like response involving RecA, membrane permeabilization, inhibiting septation, and it can also work synergistically with other antibiotics. The mechanism by which curcumin permeabilizes the bacterial membrane has been unclear. Most bacterial species contain a Mechanosensitive channel of large conductance, MscL, which serves the function of a biological emergency release valve; these large-pore channels open in response to membrane tension from osmotic shifts and, to avoid cell lysis, allow the release of solutes from the cytoplasm. Here we show that the MscL channel underlies the membrane permeabilization by curcumin as well as its synergistic properties with other antibiotics, by allowing access of antibiotics to the cytoplasm; MscL also appears to have an inhibitory role in septation, which is enhanced when activated by curcumin.

Flipper Probes for the Community

This article describes four fluorescent membrane tension probes that have been designed, synthesized, evaluated, commercialized and applied to current biology challenges in the context of the NCCR Chemical Biology. Their names are Flipper-TR®, ER Flipper-TR®, Lyso Flipper-TR®, and Mito Flipper-TR®. They are available from Spirochrome.

Mechanical stretch regulates macropinocytosis in Hydra vulgaris

Cells rely on a diverse array of engulfment processes to sense, exploit, and adapt to their environments. Macropinocytosis is a versatile example of such a process, allowing for the indiscriminate and rapid uptake of large volumes of fluid and membrane. Much of the molecular machinery essential for macropinocytosis has been well established. However, most of these studies relied on tissue culture models, leaving the regulation of this process within the context of organs and organisms unresolved. Here, we report that large-scale macropinocytosis occurs in the outer epithelial layer of the cnidarian Hydra vulgaris. Exploiting Hydra’s relatively simple body plan, we developed approaches to visualize macropinocytosis over extended periods of time in living tissue, revealing constitutive engulfment across the entire body axis. Using pharmacological perturbations, we establish a role for stretch-activated channels, including Piezo, and downstream calcium influx in inhibiting this process. Finally, we show that the direct application of planar stretch leads to calcium influx and a corresponding inhibition of macropinocytosis. Together, our approaches provide a platform for the mechanistic dissection of constitutive macropinocytosis in physiological contexts and reveal a role for macropinocytosis in responding to membrane tension.