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A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis

Brian S. Hercyk, Julie T. Rich-Robinson, Ahmad S. Mitoubsi, Marcus A. Harrell, Maitreyi E. Das

Preprint posted on 5 July 2019 https://www.biorxiv.org/content/10.1101/364786v4.full

Article now published in Journal of Cell Science at http://dx.doi.org/10.1242/jcs.236018

How do GEFs work as a team? This recent preprint by @DasLab_Pombe's group, sheds light on how fission yeast GEFs function together in order to maintain proper cell growth and division.

Selected by Leeba Ann Chacko

Categories: cell biology

Background:

Cell polarity is critical for maintaining cell shape, proper development, and thus survival of a cell; it also enables the execution of cellular tasks such as migration, neuronal firing, transport of nutrients across a cell, proper maintenance of cell-cell adhesions as well as the determination of the division plane of a cell. Due to the presence of conserved polarity markers, fission yeast is an ideal model organism to study the mechanism behind cell polarity.

The rod-shaped cells of fission yeast grow by extending their cell ends. During the cell cycle, the cells initially grow in a uni-directional manner from one end. Later, when the cells grow to a length of about 9.0-9.5 microns, they begin to grow from the ‘new end’ which came from the septum from the previous cell cycle. This uni-polar to bi-polar growth is known as ‘new end take-off’ (NETO). Finally, upon reaching a length of around 14 microns, the cells divide.

Cell division control protein 42 homolog (Cdc42), as the name suggests, is a conserved protein involved in regulating the cell cycle. Cdc42 also helps maintain cell polarity and its loss causes disruptions in both cell shape and division. Hercyk et al. were able to identify the intricate interplay between the Cdc42 activators, Gef1 and Scd1, in regulating Cdc42 activity during cell growth and division. This spatiotemporal modulation of Cdc42 activity is essential in maintaining cell shape, bipolar growth, and timely cell division.

Key findings:

Figure 1: Taken directly from Fig. 8 of Hercyk et al. 2019 under a CC-BY 4.0 international license depicting Cdc42 activators – Scd1 and Gef1, working together to ensure proper growth (bottom) and division (top) of a yeast cell.

 

1. Gef1 is required to enable cell growth to transition from monopolar to bipolar growth and this is made possible through the Gef1-mediated bipolar localization of both Scd2 and Scd1 to the poles of the cell. In the absence of Gef1, many cells show monopolar localization of both Scd2 and Scd1 and as a consequence, many of these cells grow in a monopolar fashion until cell division.

2. To understand how the Cdc42 GEFs are temporally regulated, the cell division site was used as a reference point. Hercyk et al. showed that when Gef1 localizes to the division plane, activated Cdc42 acts as an anchor for the scaffolding protein Scd2 to bind to it. The presence of Scd2 in turn recruits Scd1 to the division plane. The presence of Scd1 inhibits Gef1 at the division site post ring constriction to enable the timely separation of the daughter cells.

3. Similarly, during cell growth, Gef1 is required to activate the bipolar localization of Cdc42. In the presence of Gef1, Scd2 binds to this active Cdc42 and this, in turn, recruits Scd1 to the poles of the cell thus enabling the transition from monopolar to bipolar growth (NETO – new end take off). During cell growth, the presence of Scd1 prevents the abnormal activation of Cdc42 at the cell sides.

What I liked about this preprint:

Several players that are involved in maintaining polarity have been identified. However, the relationship between these players and the precise mechanism by which they regulate Cdc42 had not yet been elucidated. Hercyk et al. showed that the two Cdc42 GEFs, Gef1 and Scd1, spatiotemporally activate each other in order to regulate Cdc42 activity at the division site. This GEF-mediated regulation of Cdc42 is also essential to assist cell polarity during interphase after cell division has occurred.

References:

  1. Hercyk, B. S., Rich-Robinson, J. T., Mitoubsi, A. S., Harrell, M. A., & Das, M. E. (2019). A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis. bioRxiv, 9(2), 364786. http://doi.org/10.1101/364786
  2. Mitchison, J. M., & Nurse, P. (1985). Growth in cell length in the fission yeast Schizosaccharomyces pombe. Journal of Cell Science, 75(1), 357–376.
  3. Wei, B., Hercyk, B. S., Mattson, N., Mohammadi, A., Rich, J., DeBruyne, E., et al. (2016). Unique spatiotemporal activation pattern of Cdc42 by Gef1 and Scd1 promotes different events during cytokinesis. Molecular Biology of the Cell, 27(8), 1235–1245. http://doi.org/10.1091/mbc.E15-10-0700
  4. Rincón, S. A., Estravís, M., & Pérez, P. (2014). Cdc42 regulates polarized growth and cell integrity in fission yeast. Biochemical Society Transactions, 42(1), 201–205. http://doi.org/10.1042/BST20130155

 

Tags: cell-polarity, cytokinesis, pombe

Posted on: 2 August 2019 , updated on: 18 June 2021

doi: https://doi.org/10.1242/prelights.12799

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Author's response

Maitreyi E. Das shared

1. From the experiments it is clear that in the absence of Gef1, cells tend to grow in a monopolar fashion. However, it is mentioned that additionally, Gef1 deficient cells tend to be narrower – why is this the case?

In our previous work, we have shown that the cell width depends on the surface area of Cdc42 activation at the cell ends. A larger surface area of active Cdc42 leads to wider cells while a smaller surface area leads to narrower cells. This has been discussed in Das et al, 2012, PMID:    22604726 and in Das et al, 2015 PMID:26246599. In gef1Δ cells the area of active Cdc42 at the cell ends is smaller leading to narrow cell width.

2. If the presence of Gef1 is what ultimately leads to bipolar growth in cells, what is the mechanism behind precocious bipolar growth in the absence of Gef1?

In fission yeast, the old end always initiates growth first. This is the dominant end that activates Cdc42 and grows till the new end is able to recruit sufficient Cdc42 GEFs and also initiate growth. Our data indicates that Gef1 helps the new end to overcome the old end dominance and in the absence of gef1 the cell remains monopolar. The dominance of the old end depends on the growth history of that end. If an end has grown in one generation, it will be dominant in the next generation after the cells divide. If the end did not grow in the previous generation—as seen in monopolar cells—then that end does not have a growth history and is not dominant. A daughter cell that inherits this non-growing end does not need to overcome any dominance at the old end and the new ends start growing at the same time as the old end in these cells. This results in precociously bipolar cells. ­

3. The scd1 delta cells appear much smaller and rounded compared to Scd1+ cells. Due to their rounded shape, it is evident that these cells do not contain ‘poles’ and as a consequence, it is expected that Gef1 and Scd2 localization will not be at the poles (since they do not exist) like in the Scd1+ and will appear to be localized in ‘random’ locations. 

a) How do you ascertain that the ‘patch-like’ localization of Gef1 and Scd2 is not merely an effect of the change in cell shape?

Our data shows that in the absence of scd1, Gef1 localization at the cell membrane is more prominent and appears as random patches. This indicates that once the cell can no longer maintain shape due to Scd1-mediated polarization, Gef1 is mis-regulated. We have not shown if Scd1 directly regulates Gef1 or if this is via some downstream pathway. It is important to consider here that the change in cell shape is due to random localization of Gef1. Gef1 when randomly localized, activates Cdc42 ectopically and this results in a depolarized cell shape. This has been discussed in our previous papers Das et al, 2009, PMID:19646873 and Das et al, 2015 PMID:26246599.

b) Why would the shape of the cell change in the absence of Scd1?

 Cell polarization requires a positive feedback loop of growth activation. In fission yeast this is mediated by Scd1 and Scd2 that form a complex with Cdc42. This positive feedback maintains the Cdc42 activation at the cell poles resulting in the rod-like cell shape. In an scd1Δ mutant, the positive feedback is lost and the cell are depolarized.

4. It has been shown that by disrupting the actin cytoskeleton (through LatA treatment), the localization of Cdc42 and Gef1 can be largely perturbed. This in turn would disrupt the localization of Scd2 and subsequently Scd1. Why does deleting Scd1 affect the actin network? What is the specific role of Scd1 in regulating the localization of actin?

Scd1 activates Cdc42 which then activates the formin For3 to promote actin polymerization (Martin et al, 2007, PMID: 17699595). When Cdc42 activation is maintained at the cell ends due to Scd1 dependent activation, the actin remains polarized. In the absence of scd1, For3 is activated by ectopic Gef1-dependent Cdc42 activation and this results in disorganization of the actin network.

While actin disruption by LatA leads to mis-localization of Gef1 and Scd2, we did not show that it leads to mis-localization of Scd1. We find that, similar to previous reports (Kelly and Nurse, 2011, PMID: 21849474) upon LatA treatment, Scd1 fails to localize to the cell cortex. It is possible that mis-localization of Gef1 upon LatA treatment is due to loss of Scd1 from the cortex, since scd1Δ mutants also show mis-localized Gef1. More detailed investigation into mis-localization of Gef1 in the future will explain this.

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