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. Vidur Sabharwal is first author on ‘ F-box protein FBXB-65 regulates anterograde transport of the kinesin-3 motor UNC-104 through a PTM near its cargo-binding PH domain’, published in JCS. Vidur conducted the research described in this article while a PhD student in Sandhya P. Koushika's lab at the Tata Institute of Fundamental Research, Mumbai, India. He is now a postdoc in the lab of Abdel El Manira at Karolinska Institutet, Stockholm, Sweden, where he works to understand and describe how complex observations in biological systems emerge from simple underlying mechanisms.
Vidur Sabharwal
How would you explain the main findings of your paper in lay terms?
Transport in neurons occurs over large distances, which can be up to a maximum of 1 m in humans. There are a variety of molecular motor proteins called kinesins that drive cargo over these vast distances, like trains. However, just as trains are coordinated on tracks, kinesins must also be coordinated within the neuron to deliver the correct cargo to the right destination in sufficient amounts. Thus, we wanted to figure out how these motors are regulated to drive transport.
We discovered that a particular kinesin, UNC-104, is regulated in the neurons by a modification that prevents its association with cargo. Trains can also encounter challenges, such as moving uphill, and more engines could be added to the train to ensure smooth travel. Similarly, we found that unmodified kinesins were more highly associated with cargo and aided in cargo transport. However, regulation is key, and persistent association of unmodified motors with cargoes led to misrouting of cargo towards wrong destinations. Thus, this modification can dynamically fine tune the activity of the motor to drive sufficient transport towards the right destination.
Were there any specific challenges associated with this project? If so, how did you overcome them?
C. elegans is a unique model organism. While it has multiple benefits, there were two main challenges that were associated with this project. Firstly, given that we focused on the nervous system of the worm, which constitutes a minor fraction of the total worm volume, biochemical experiments to nail down the precise nature of the post-translational modification using traditional approaches were challenging. Thus, we deleted the modified region of UNC-104 and showed the effects of this deletion in worms. To understand the consequences of this modification, we set up a collaboration with theorists Prof. Amitabha Nandi, Prof. Debasish Chaudhuri and Dr Amir Shee. Using new biophysical methods in a genetics lab was a challenge as well, but this was ultimately overcome through the support and faith that Prof. Sandhya Koushika placed in me and the consistent supportive discussions and idea sharing between us. This led to exploration of novel directions that I had not previously imagined. Together, we managed to understand the theoretical basis of increased motor affinity to cargo, which likely arises due to the motors' increased binding rates. This led to the second main challenge, when we concentrated on a family of modifier proteins called E3 ligases. Although humans have ∼200 E3s, C. elegans have over 600. We decided to focus only on the subset of E3s that were appreciably expressed within neurons in C. elegans. It's a fascinating family of proteins where a lot remains to be discovered.
Why did you choose Journal of Cell Science for your paper?
The Company of Biologists have supported all three Indian C. elegans meetings which I have attended and have given tremendous support to this community and to aiding the career progression of junior researchers. Further, we had heard that the review process is fast and thoughtful, which we found to be true in our experience. Finally, I am very excited to get our own tree associated with this manuscript, which will be viewable in the Forest of Biologists.
A maximum intensity projection of biofluorescence complementation between UNC-104 and FBXB-65 in the head of C. elegans reveals an interaction between the two throughout different regions of neurons. The red arrow indicates a cluster of cell bodies and the green arrow indicates the end of a neuronal process.
A maximum intensity projection of biofluorescence complementation between UNC-104 and FBXB-65 in the head of C. elegans reveals an interaction between the two throughout different regions of neurons. The red arrow indicates a cluster of cell bodies and the green arrow indicates the end of a neuronal process.
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?
I have always been interested in understanding the things around me. However, in high school, I first started to realize how fascinating and complex biology really is. This fascination was further nurtured during my undergraduate training. A group of friends and I would do simple experiments after classes in the open labs after we befriended the technicians there. Some of the most fun and interesting times I had before my PhD were in various hackathons and brainstorming sessions, along with the summer internship I did at the Indian Institutes of Science Education and Research (IISER), Mohali under Dr Chandan Sahi. During my PhD, I enjoyed science outreach sessions called ‘Chai and Why?’ hosted by Prof. Arnab Bhattacharya and Surendra Kulkarni. I made a lot of friends and had interesting discussions with students at the Tata Institute of Fundamental Research (TIFR) from various other departments and fields. In the Koushika lab, we had fun times where we would celebrate Mendel Day, Sushruta Jayanti (known as the ‘father of surgery’) and other scientists by discussing their seminal papers. I deeply appreciate all these memories that have led me to this point in my career, and I continue to find science a lot of fun.
What's next for you?
I have changed scientific gears and begun my postdoc in an electrophysiology lab. Here, I will study the neuronal circuits that guide rhythmic movement in zebrafish. I would like to continue developing new methods and combining theoretical approaches to bring new understanding of biological observations.
Tell us something interesting about yourself that wouldn't be on your CV
I am a big foodie and love to explore interesting cuisines. Also, I am very fond of leisure cycling in my time off.
Vidur Sabharwal’s contact details: Karolinska Institutet, Solnavägen 9, 17165 Stockholm, Sweden.
E-mail: [email protected]
