Cell patterning by secretion-induced plasma membrane flows
Posted on: 21 January 2021
Preprint posted on 20 December 2020
Article now published in Science Advances at http://dx.doi.org/10.1126/sciadv.abg6718
Rga4, a Cdc42 GAP, goes with the flow: constraining Cdc42 activity to the growing tips of fission yeast depends on membrane flows, and the slow diffusion and low detachment rate of Rga4 in the membrane.
Selected by Helen Zenner
Categories: cell biology, developmental biology
Introduction
Patterning of both proteins and lipids in the plasma membrane is essential for establishing and maintaining all different types of cell polarity. Of course, this is not a static process, but is instead driven by numerous feedback loops such as the antagonistic relationship of the canonical polarity factors, the Par complex and Scribble complex . In addition, this pattern must be maintained in the face of extensive membrane flows, particularly during cell migration and cell growth, where membrane is added via exocytosis to the leading edge or growth site respectively, and removed by endocytosis. Membrane flows within the plasma membrane maintain the correct tension in the face of vesicular trafficking. In theory, these membrane flows could either enhance or disrupt cell patterning, or play no role at all.
In this preprint, Gerganova and colleagues use a powerful combination of computer simulations, optogenetics, synthetic probes and yeast genetics to test whether membrane flows contribute to patterning in polarised cells.
Key Findings
The authors create a perfect test bed for combining their computational simulations with in vivo measurements. In fission yeast, growth occurs at the tips of the rod-shaped cells, where rates of both endocytosis and exocytosis and thus membrane flows are high. The key findings are as follows:
- After uniform recruitment and oligomerisation at the plasma membrane, an exogenous membrane-associated protein is excluded from the tips within 5 minutes and accumulates in lateral peaks.
- This is dependent on secretion, but not endocytosis (or actin).
- In terms of membrane behaviour, the main conditions for protein exclusion in the computer simulations was that the exocytic zone is smaller than the endocytic zone. This was calculated from experimental measurements in this study.
- Whether a protein is excluded from the poles depends on its lateral diffusion rates and exchange with the cytoplasm where only proteins with slow diffusion rates, and/or low detachment rates are coupled to lateral flows.
- Proteins that are highly oligomerised have slower diffusion rates
- The distribution of the Cdc42 GAP Rga4 is established by membrane flows. This can be altered by reducing oligomerisation or varying detachment rates via the protein’s coiled-coil and cortex binding domains respectively.
- In round yeast cells, lacking endogenous Cdc42 GAPs, adding the Rga4 GAP domain to a protein that oligomerises and has a low detachment rate is sufficient to rescue the restricted Cdc42 activity, polarised growth and rod-shaped morphology.
Overall, these data show membrane flows contribute to the regulation of Cdc42 activity and thus polarised growth and cell patterning. In their mathematical model the authors combine measurements from the literature and their own experimental data to describe the behaviour of the plasma membrane and the proteins associated with it. The model is then tested in vivo in well-designed experiments using both synthetic probes and an endogenous-like protein.
Questions for the authors
- A number of endocytic parameters are incorporated in the model including the relative size of the endocytic zone, but experimentally it doesn’t seem to be important. What could be the explanation for this?
- Is the localisation of Rga4 in lateral peaks functionally important?
- Septins are linked to both Cdc42 and membrane organisation, could they have a role in patterning via membrane flows either at the growing tips or during cytokinesis?
For more information
Establishing and maintaining polarity https://www.sciencedirect.com/science/article/pii/S0022283618305795?via%3Dihub
Membrane flows in migrating Dicty https://www.nature.com/articles/s41598-017-13438-5
Cdc42 activity in fission yeast (and the optogenetic system used) https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000600
doi: https://doi.org/10.1242/prelights.27085
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4 years
Sophie Martin
Some thoughts on the interesting questions raised:
1. We can manipulate cells to have no apparent endocytosis (at least no actin patches), but naturally all cells have endocytosis, so it makes sense to model the phenomenon in presence of endocytosis. When endocytosis is blocked, it is likely that it also affects the rate of exocytosis (for instance through feedback control on plasma membrane tension, or through changes in recycling compartments). We do not exactly know how the cell copes in this condition.
2. Is the localisation of Rga4 in lateral peaks functionally important? This is an interesting question for which we do not have an answer. The lateral peaks may be a simple consequence of the flow without direct functional value, but it is also possible it helps keep Rga4 in some cellular regions with consequence on future cell history (for instance effects on division, or inheritance in daughter cells).
3. The role of septins is not prominent during polarized growth in rod-shaped fission yeast. So although we have not looked at their possible roles in flow-dependent patterning, I suspect they are not important. This may be different in S. cerevisiae, where septins are critical to shape the bud neck through a mechanism that may well involve membrane flows (see for instance Okada et al, Dev Cell 2013).