ABSTRACT
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. Heather Baker is first author on ‘ The co-chaperone DNAJA2 buffers proteasomal degradation of cytosolic proteins with missense mutations’, published in JCS. Heather is a PhD student in the lab of Thibault Mayor at University of British Columbia, Vancouver, Canada, investigating cytosolic protein quality control.
Heather Baker
How would you explain the main findings of your paper in lay terms?
Like any good manufacturing process, the process of protein synthesis has quality control systems in place to catch mistakes. In this work, we set out to better understand how cytosolic proteins with missense mutations are targeted for destruction by our cells. We first identified a panel of disease-associated missense mutant proteins with cytosolic localization that are targets of the ubiquitin proteasome system, a major pathway that cells use to breakdown proteins. We selected one of these mutants and carried out a proximity labelling experiment to identify proteins that interact with the mutant protein more than with its wild-type counterpart. Notably, we identified the co-chaperone DNAJA2. We validated that DNAJA2 interacts with our mutant protein and, when DNAJA2 was knocked out, we saw an increase in degradation of the mutant. This suggests that DNAJA2 stabilizes the mutant and prevents it from being broken down. When we looked to see if this effect was also the case with the remaining panel of mutants, we saw that this only applied to a few of the other mutants. In these cases, DNAJA2 was important for stabilizing both the mutant and wild-type proteins. These results highlight that DNAJA2 has various roles in protein quality control.
When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?
Seeing that knocking out DNAJA2 had no impact on the turnover of the wild-type model protein substrate and that the stabilizing effect was exclusive to the mutant protein was quite striking. It validated our BioID proximity labelling experiment, which showed DNAJA2 was significantly enriched with the mutant protein. I wasn't certain that DNAJA2 knockout had no impact on the wild-type protein until I saw the flow cytometry data that demonstrated this.
Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?
First, my PI, Prof. Thibault Mayor, has been a great mentor throughout my PhD. He has always pushed me to think a little bit out of the box and consider how important it is to communicate the story behind the research. One of the co-authors of this manuscript, Dr Jon Bernardini, has also been extremely supportive throughout my PhD. Although we only crossed paths in the lab for a brief time, he has continued to be an important mentor to me. I've learned a lot from his outlook on science – especially from his love of teamwork and his ability to lift others up.
Mutant TPMT is stabilized by DNAJA2. Flow cytometry histograms show cells with (+/+) and without (−/−) DNAJA2 expressing either the TPMT wild-type or mutant reporter. A decreased mClover2:mRFP1 ratio indicates that the TPMT reporter is being degraded. Cells that are DNAJA2 deficient (purple, pink) show increased turnover of the TPMT mutant, but no effect on wild-type TPMT.
Mutant TPMT is stabilized by DNAJA2. Flow cytometry histograms show cells with (+/+) and without (−/−) DNAJA2 expressing either the TPMT wild-type or mutant reporter. A decreased mClover2:mRFP1 ratio indicates that the TPMT reporter is being degraded. Cells that are DNAJA2 deficient (purple, pink) show increased turnover of the TPMT mutant, but no effect on wild-type TPMT.
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?
After dipping my toes into research in my second year of my undergraduate degree, I was hooked. It was so exciting to work towards answering a particular research question. It was even more exciting to gradually learn about and master techniques that could aid in answering those questions. I just wanted to continue to learn, so grad school seemed like the next logical choice. Moving to a different province to pursue my PhD was the most exciting moment on this path and, 5 years in, I'm glad I made the leap!
Who are your role models in science? Why?
My role models in science include Drs Annie Ciernia and Sheila Teves, both professors in my department. Beyond being accomplished scientists, they have taken meaningful steps to improve equity, diversity and inclusion within our community, which I find incredibly inspiring. Another role model of mine is my best friend, Tess Lamer, who is also pursuing her PhD. Tess is one of the most brilliant and hardworking people I know, with a CV that reflects her dedication and talent. Her unmatched work ethic and determination inspire me – I truly believe she could accomplish anything she sets her mind to.
What's next for you?
I'm looking to finish up my PhD next year and then hit the job market! There are so many exciting opportunities and lots of cutting-edge research in biotech right now. I'm really looking forward to seeing what the future holds.
Tell us something interesting about yourself that wouldn't be on your CV
I really enjoy spending time outdoors and I feel incredibly fortunate to be pursuing my PhD in Vancouver, where nature is just a step away. The city offers amazing access to hiking trails, ski mountains and beaches perfect for volleyball – my favourite ways to relax and recharge after a long week in the lab.
Heather Baker’s contact details: University of British Columbia, Vancouver, BC V6T 1Z4, Canada. E-mail: [email protected]
