First person – Jianhui Li

Jianhui Li

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

We are interested in understanding how cells regulate proteasome trafficking and degradation. The ubiquitin–proteasome system (UPS) touches on almost every aspect of cellular processes and is central to protein homeostasis in health. Dysfunction of the UPS has been implicated in the pathogenesis of many human diseases, including various cancers and neurodegenerative disorders. Proteasomes are highly enriched in the nucleus in yeast and most mammalian cells under nutrient-rich conditions but relocate to the cytoplasm and form proteasome storage granules (PSGs) under glucose-starvation conditions. PSGs dissipate rapidly and proteasomes are reimported to the nucleus upon glucose refeeding of cells. In this paper, we have demonstrated that the endosomal sorting complex required for transport (ESCRT)-dependent microautophagy pathway fine-tunes proteasome quality control by selectively degrading aberrant proteasomes so that normal proteasomes are stored in PSGs and readily available once nutrient-rich conditions are restored. ESCRTs are highly conserved multi-subunit complexes involved in numerous cellular processes through cargo protein recognition and membrane remodeling abilities. We hope a precise understanding of proteasome quality control, especially under stress conditions, could provide valuable therapeutic targets for drug development in human disease treatment.

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

In this project, we had genetic, biochemical and cell biological data that led us to the hypothesis of selective microautophagy of inactive proteasomes. To help prove this, we needed to demonstrate a specific interaction between the ESCRT-0 subunit Vps27 and aberrant proteasomes. There was a technical challenge to detect Vps27–proteasome interaction in cells under low-glucose conditions because we found that Vps27 is itself largely degraded and the interaction is likely transient. To overcome this, I tried in vitro pulldowns with recombinant Vps27 and purified proteasomes, but it did not work. Following discussions with my advisor Dr Mark Hochstrasser and a former graduate student in the lab, Dr Chin Leng Cheng, I developed a protocol for in vivo overexpression of Vps27, and this time it worked. The same idea can be adapted to address many other questions with a similar limitation. This is an example of how a novel idea or technical advancement usually can bring breakthroughs in the field.

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

I would say there were a number of small eureka moments, such as when I realized that during glucose starvation not all proteasomes were going to PSGs but were being degraded by the poorly understood process of microautophagy, or the finding that ESCRT-0 binding is important for sorting aberrant proteasomes to the vacuole.

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

Journal of Cell Science has a rigorous and fair review process, is completely free to publish and promotes high-quality papers in the cell biology field. My PhD work on viral protein trafficking (Li et al., 2016; doi:10.1242/jcs.190082) and our lab's previous work on proteasome nuclear import (Budenholzer et al., 2020; doi:10.1242/jcs.236158) were also published in Journal of Cell Science. It's a great place for cell biologists to share their exciting findings and reach out to a broader readership.

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

I have many great people who have helped me in various ways throughout my research and career development. I would like to thank them first. Among them, my postdoc advisor, Dr Mark Hochstrasser, and my PhD advisor, Dr Xiaofeng Wang, have been significant mentors. They provided me with the freedom to pursue my research interests, encouraged me when things in my life were not great, and offered invaluable suggestions and unconditional support to advance my career and professional development.

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?

The fulfilment of scientific discoveries and a supportive family. The scientific discovery process is challenging and requires lots of energy and time. It would be impossible for me to be fully dedicated to my research without a supportive family. The most important moment that led me to where I am now is the decision we, Ms Tingting Sun and I, made to build up a family during my first year of master's study. My wife, Tingting, takes care of our family in all routine and essential aspects, giving me an unlimited energy source to pursue my career goals and a heartwarming harbor to rest.

Who are your role models in science? Why?

I do not have specific role models in science, because every single scientist whom I can learn from has been a role model. I am deeply inspired and motivated by their persistence in scientific endeavors, and by their willingness to help others, especially early-career scientists, and to promote the future of science.

What's next for you?

I'm searching for a faculty position to establish my independent lab as the next step of my career development.

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

I like to be together with my family doing nothing or anything. I am being challenged all the time by my son with all kinds of questions about science, and often I do not know the answers. I am so happy to see his interest and curiosity about science and nature.