First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Norbert Volkmar is first author on ‘The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis’, published in JCS. Norbert conducted the research described in this article while a DPhil student in John Christianson's lab at the Ludwig Institute for Cancer Research, University of Oxford, UK. He is now a postdoctoral researcher in the lab of Paul Lehner at the Cambridge Institute for Medical Research, University of Cambridge, UK, investigating researching the fundamental mechanisms of cellular protein and lipid homeostasis.
How would you explain the main findings of your paper in lay terms?
Many proteins reside within cell membranes where they perform a myriad of essential functions. The production of such transmembrane proteins by the cell requires complex molecular machines that facilitate insertion into the membrane. We found that one such molecular machine, the ER membrane protein complex (EMC), enables the correct synthesis of at least two essential transmembrane proteins that maintain appropriate levels of cellular cholesterol. Every cell tightly maintains its cholesterol content within a narrow range as both depletion or excess of this lipid are toxic. Of these two EMC-dependent proteins, squalene synthase (SQS) is essential for cholesterol production, whereas sterol O-acyltransferase 1 (SOAT1), detoxifies surplus cholesterol. When we genetically deleted the EMC, cells became unable to robustly tolerate fluctuations in cholesterol levels and were sensitised to cell death when exposed to high or low cholesterol environments. Our study demonstrates that the EMC is tightly embedded in multiple cellular pathways because it enables the production of crucial membrane proteins performing vital cellular functions.
A major challenge for me certainly was the initial obscurity of the EMC.
Were there any specific challenges associated with this project? If so, how did you overcome them?
This project was demanding on multiple levels. A major challenge for me certainly was the initial obscurity of the EMC. When I started out on this project, not much was known about this evolutionarily conserved protein complex and the diverse molecular phenotypes complicated interpreting its cellular function(s). I therefore approached this project with an open mind and was soon heading towards the field of lipid biology and cholesterol homeostasis, areas our lab had previously not specialised in. This is where the value and excitement of scientific collaboration bore out as I was privileged to closely work with experts in fields of proteomics (Benedikt Kessler lab), lipidomics (Daniel Nomura lab) and protein biogenesis (Hegde lab). It was really this collaborative effort that shaped the many facets of the project.
When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?
Perhaps one of my earliest critical findings was the result from systematically depleting each of the ten EMC subunits: It showed that the loss of a single component led to the complete destabilisation of the entire complex. This was remarkable and enabled me to perform an efficient EMC knockout, thus laying the foundation of this project. The second catalyst was a number of phenotypic assays that suggested a clear link between the EMC and cellular cholesterol homeostasis.
Why did you choose Journal of Cell Science for your paper?
Journal of Cell Science is a high-quality journal that addresses a broad audience of cell biologists. I therefore believe that the deep involvement of the EMC in fundamental cellular pathways renders Journal of Cell Science an ideal platform to promote our work.
Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?
I am grateful to my supervisor John Christianson, who, beyond direct supervision, enabled me to tap into a rich and open network of collaborators. This helped me greatly in expanding and realising my vision. I am particularly obliged to the many fruitful discussions with Manu Hegde and Liz Miller at the LMB in Cambridge (UK), who were incredibly supportive and inspiring.
I have always considered it a privilege to be able to earn a living with the pursuit of a goal that deeply motivates me.
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 considered it a privilege to be able to earn a living in the pursuit of a goal that deeply motivates me. The endeavour of discovery and creating knowledge is an inestimable opportunity not only to contribute to the way we understand the world around us, but also to leave behind something of value. Since an early age, I have been fascinated with biology and exploring the microscopic universe that is the cell. This is a journey that can at times be difficult and frustrating, but it still fills me with excitement and joy.
Tell us something interesting about yourself that wouldn't be on your CV
I think part of the reason why I chose science as a career path is a deeply rooted passion for creating with my own hands. For me personally, creating art such as drawings and paintings is a highly rewarding experience and one of my favourite pastimes. I try to incorporate this creative element in my research and it is great fun drawing many illustrations by hand – be it for the next scientific presentation or conference poster!
Norbert Volkmar's contact details: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY.