First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Rachel Wills is first author on ‘ A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane’, published in JCS. Rachel conducted the research described in this article while a PhD student in Gerry Hammond's lab at University of Pittsburgh. She is now a postdoc in the lab of Jason Lohmueller at the University of Pittsburgh, USA, investigating how basic cellular mechanisms contribute to diseases at the organismal level.

Rachel Wills

How would you explain the main findings of your paper in lay terms?

The inner leaflet of the plasma membrane is a bustling hub of cellular activity. A vast amount of this activity is regulated by a specialized phospholipid, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. It remains unclear how cells can both sense and maintain homeostasis of PI(4,5)P2 levels. This manuscript shows that an enzyme capable of synthesizing PI(4,5)P2, PIP4K, also functions to sense and maintain levels of PI(4,5)P2.

We can relate the way this enzyme acts to the way a thermostat acts. If we think of the cell's specific set point of PI(4,5)P2 as if it were temperature, then we can break down both the complicated biology of phospholipid homeostasis as well as the rheostatic nature of this process. We can think of PIP5K [the major PI(4,5)P2-producing enzyme in the cell] as the ‘furnace or air conditioner’ (depending on the season) that can increase or decrease PI(4,5)P2 levels as needed. The ‘thermostat’ can then sense the internal temperature and signal to the temperature regulator to turn off. We believe that PIP4K acts as this cellular thermostat for PI(4,5)P2, and is capable of both sensing PI(4,5)P2 levels and turning off PIP5K activity.

Were there any specific challenges associated with this project? If so, how did you overcome them?

While the work for this manuscript was being carried out, another lab published work that at first glance, supported our hypotheses and negated our hard work. However, after long conversations to deeply understand the work presented, we came to realize that there were still important core questions remaining that I felt both equipped and excited to address. It was important to me to reframe the questions considering the new work published and to recapitulate what the other lab was able to demonstrate, but with different methods.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

We had been struggling to generate PIP5K protein throughout the duration of this project. At the American Society for Cell Biology meeting in 2017 we saw Scott Hansen give a brilliant talk about how he was able to generate PIP5K protein and visualize kinase activity on supported lipid bilayers. We quickly formed a collaboration and were able to use Scott's expertise and data in this manuscript, combining his biochemical data with our data from live cells to demonstrate our hypothesis in multiple systems.

Why did you choose Journal of Cell Science for your paper?

The journal has a long history of publishing important phosphoinositide and cell biology research. Furthermore, the Journal of Cell Science offers open access publishing, which can help to ensure that our work is seen by a wide audience and that it has the potential to make a real impact on the scientific community.

Acute enrichment of PI(4,5)P2 causes endogenously tagged PIP4K2C to increase association with the membrane.

Acute enrichment of PI(4,5)P2 causes endogenously tagged PIP4K2C to increase association with the membrane.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

Gerry has been a phenomenal mentor during this entire process, really helping guide me to become the overall scientist I am today. Additionally, my thesis committee was always full of insight and wonderful guidance. Marijn Ford and Linton Traub were always interested in having impromptu hallway conversations about experiments I was running or data I had generated. And finally, before I started graduate school, I worked as a research technician with Erin Kershaw, who pushed me to pursue my goal of getting into graduate school.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

As a kid, I spent my time playing with Legos and K'NEX toys. It helped me realize that many tiny pieces come together to create large and complex structures. I quickly realized that each piece was essential and if one piece is out of order an entire structure can cease to function properly. My journey through research has been much the same. As a technician, my research focused on a small number of critical cell cycle modulators and understanding how the localization of these molecules could influence the proliferative capacity of cells. Although I enjoyed this work, I wished to study biology at a physiological level. As such, in my next position, I worked to use cell and lipid biology to understand metabolic syndrome at an organismal level. Eventually, I realized that understanding the basic cell biology behind metabolic syndrome was important to the understanding of disease, and again moved back into cellular biology in Dr Gerry Hammond's lab.

What's next for you?

I am presently pursuing a postdoctoral experience to combine my love for microscopy, lipids and cellular signaling.

Tell us something interesting about yourself that wouldn't be on your CV

First, I have a PI(4,5)P2 tattoo (a PIPtoo if you will) on my right forearm. Second, during the pandemic I started to dabble in the hobby of 3D printing.

Rachel Wills's contact details: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.


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A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane
J. Cell Sci