Arun Radhakrishnan, currently a professor at the Department of Molecular Genetics at UT Southwestern Medical Center, conducts research on the role of membrane cholesterol in regulating cell growth, lipid homeostasis, and immune defense against microbial infections. We had the opportunity to correspond with Arun in advance of his research seminar on Tuesday, January 28th, to gain insights into his scientific journey.
Can you share your journey from starting as a trainee to your current tenure-track position? Were there any specific moments or individuals who inspired your passion for curiosity-driven research?
- I started in chemistry, focusing on the physical chemistry of liquids, of which lipid membranes are an example. My mentor, Harden McConnell, introduced me to the peculiar properties that cholesterol endows to membranes. When I finished my trainee phase, he strongly recommended I pursue a career in cell biology, which I trusted. He reached out to Brown and Goldstein and that is where I landed for my postdoctoral research. After my fellowship, I secured an academic position and later worked in industry. I eventually returned to Dallas, where I hold my current position. I explored various options before settling on a career that allowed me to study cholesterol from both chemical and cell biological perspectives.
What is it like working with Brown and Goldstein?
- Brown and Goldstein are impressive and remarkable in many ways and it was an intense and rewarding experience working with them as a trainee. One of their most remarkable attributes is their unwavering focus on a problem. I try to emulate that level of focus in my own research.
What are the most exciting projects that you are currently undertaking in your laboratory, and what are the significant research questions that you are pursuing in the field of cholesterol biology?
- I’ve studied cholesterol biology for a long time. In particular, I have been focused on understanding how membrane proteins sense membrane composition. When studying membrane proteins by biochemical methods, we often remove the membrane and replace it with a detergent, and then speculate as to how the membrane protein functions in their original environment, the membrane. But, this approach can only take us so far and we have turned more and more towards understanding the membrane itself. Over the past five years, we have turned our attention to toxin proteins produced by bacteria and fungi that recognize specific lipids that host cells have that they don’t have, like cholesterol and sphingomyelin. These pathogens then use this lipid-sensing interaction to attack and enter the host cell. Interesting to us is that these toxin sensors are soluble proteins, not membrane proteins, and therefore can be studied in the context of membranes without disrupting the membrane. Surprisingly, we discovered that these bacterial and fungal proteins can sense different lipids in a membrane with the exact same sensitivity and specificity as mammalian eukaryotic lipid-sensing proteins. We’ve been able to exploit these similarities to identify small-molecule inhibitors of these complex membrane proteins. This is exciting and has launched new directions for our research. Moreover, these studies reveal an additional level of regulation of lipid pathways by lipid-lipid interactions. These pathways extend beyond cholesterol regulation, our original area of research, to cell growth pathways like Hedgehog signaling as well as immune signaling pathways. These new connections are an exciting new direction for us.
What do you think are the primary challenges that the field encounters when investigating cholesterol biology?
- To fully understand cholesterol biology, we must delve deeper into how the relevant sensor proteins interact with the membrane and sense cholesterol. We need to study the proteins as well as the membranes that they live in. As technology advances, this will become more and more feasible. As one example of this, we have recently been able to study the interaction between sphingomyelin and cholesterol in a membrane at the atomic level using one of the microbial lipid-sensing proteins that I described earlier.
Do you have any notable “Eureka” moments that have shaped your research?
- In one recent study, we measured the response of the cholesterol sensor in animal cells, an ER membrane protein called SCAP, to changes in ER cholesterol levels. We found that SCAP’s response was switch-like, with no binding to ER cholesterol when the level was below ~5 mole% of ER lipids, and robust binding above this switch-point. Out of curiosity more than anything, we measured the binding of these bacterial cholesterol sensors that I have mentioned to ER membranes. We were shocked when we found that these bacterial proteins bind cholesterol in the ER membrane at the exact same concentration where SCAP gets activated. I would not have guessed that at all. There is nothing common between the structures of the soluble bacterial protein and the human integral membrane protein Scap. So, what is common? It's the membrane. That’s what ultimately got us to suspect that there’s a membrane property that controls these interactions and led to the identification of a specific small-molecule inhibitor of Scap.
Outside of scientific pursuits, do you engage in any hobbies or activities that you find enjoyable, whether alone or with your laboratory colleagues?
- I love traveling, and I cherish the opportunity to spend quality time with my family during these journeys.
What advice would you offer to early-career scientists?
- For me, the critical step was finding mentors whom I genuinely respected and admired. I trusted them to guide my path, and it has worked out. So, I would say to choose your mentors carefully. Also, once you pick a problem that you are interested in – for me it was cholesterol biology – then go out and learn whatever skills you need to help answer that question, even if it means changing disciplines.