Holes in the plasma membrane trigger the activation of the Torso receptor tyrosine kinase.
As a general rule, cells don’t do well when holes are poked in their plasma membranes. That’s why many immune cells use enzymes like perforin to puncture the membranes of pathogenic cells, dysregulating and often killing them. However, a new report in GENETICS by Mineo et al. suggests that creating holes in the plasma membrane might be a normal and necessary process during development.
The authors were interested in whether membrane hole-punching could play a role in activation of a receptor tyrosine kinase known as Torso. Torso is crucial for development of the fruit fly Drosophila melanogaster and is activated at both poles of the developing embryo. Torso activation depends on the polar accumulation of Torso-like (Tsl), which is the only Drosophila protein known to have a Membrane Attack Complex/Perforin domain. This domain is often present in proteins that perforate cell membranes, so the authors hypothesized that Tsl’s function might be to create membrane pores and, therefore, that simply pricking holes in the cell membrane might substitute for its function.
To test their hypothesis, Mineo et al. studied mutant embryos that either lacked the Tsl protein entirely or carried a non-functional version; both mutants exhibit several easily observable developmental defects. At this stage of development, the embryos are syncytial, which means all the dividing nuclei share a common cytoplasm and are surrounded by a single cell membrane. The researchers poked holes in the membrane at the poles of the embryo using sharpened capillaries of the type sometimes used to inject DNA for genetic engineering. Remarkably, embryos that had holes poked in them had fewer defects than their un-poked counterparts, suggesting that the mechanical formation of holes partially compensate for Tsl function.
To determine whether the rescue was due to mechanical stress on the membrane—but not necessarily the holes themselves—the authors then prodded membranes but did not puncture them. Prodded embryos showed the same developmental defects as their untreated counterparts, showing that an actual rupture in the membrane was required to rescue the developmental phenotype in Tsl-deficient fly embryos.
The authors also demonstrated that Torso signaling is required for the rescue effect of these membrane holes; fly embryos lacking Torso or its ligand, Trunk, did not show any change in developmental phenotypes when they were mechanically punctured. The location of the holes also mattered; the rescue was greatly diminished when the holes were created in the middle of the embryos, rather than at their poles.
Overall, the results suggest that Tsl spatiotemporally regulates Torso signaling by puncturing the cell membrane. These punctures are presumably needed for the exchange of a molecular signal between the interior of the embryo and its extracellular surroundings; it remains to be seen exactly how activation by Tsl works. What is clear is that, sometimes, all that’s needed to keep development on track is a sharp punch in the membrane.
CITATION:
Holes in the Plasma Membrane Mimic Torso-Like Perforin in Torso Tyrosine Kinase Receptor Activation in the Drosophila Embryo
Alessandro Mineo, Esther Fuentes, Marc Furriols, Jordi Casanova
; https://doi.org/10.1534/genetics.118.301397
http://www.genetics.org/content/210/1/257
Science Writing and Communications Intern, Genetics Society of America.
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