Liang Ge pursued his PhD in the lab of Dr Bao-Liang Song at the Institutes of Biochemistry and Cell Biology, Chinese Academy of Sciences, where he studied the molecular mechanisms of cholesterol absorption. In 2011 he moved to California for a postdoc and later a research specialist position with Randy Schekman at the University of California, Berkeley. There, he discovered key roles for LC3 lipidation and the ER–Golgi intermediate compartment in autophagosome biogenesis. Liang established his group in the School of Life Sciences at Tsinghua University at the end of 2017, where he combines cell biology and biochemistry techniques, mouse models and computational biology to study the mechanisms of autophagy and unconventional protein secretion.
What inspired you to become a scientist?
My passion for science came from my father, who is a professor devoted to his career and who also loves nature. Then, during my scientific career, I was lucky to have great mentors who fully encouraged me to pursue my curiosity in science: Dr Bao-Liang Song, who is now a well-known scientist in the field of cholesterol metabolism, during my graduate research and Dr Randy Schekman during my postdoc, who is respected as a gentle and generous mentor and is of course amongst the best cell biologists in the field of membrane trafficking.
In the Schekman lab, you were investigating one of the big questions in the autophagy field: finding the membrane origin for autophagosome formation. Could you tell us how you started off the project and your key experiments that provided insight into this question?
When I joined the Schekman lab, Randy sent me the latest paper from his group, in which a smart postdoc, Dr Jason Lam, established a cell-free reconstitution assay and showed that the endoplasmic reticulum (ER) buds vesicles that contain membrane proteins of the peroxisome. I expressed my strong appreciation for the beautiful biochemical assays, and also joked – since Randy likes joking – that it would be interesting to develop such assays to test whether the ER buds vesicles for lipid droplets and autophagosomes as well. The joke led me to my first project, which was establishing a cell-free ER-budding assay and measuring autophagosome precursor generation. However, this nearly failed due to the lack of a specific autophagic membrane protein that would faithfully reflect the budding process from the ER. I observed, however, that an enzymatic process called LC3 lipidation, which is considered to reflect autophagosome biogenesis, could be recapitulated in our assay, and this became the centre of my work for the following six years. Then, to look at the membrane origin I developed a membrane fractionation assay and found that instead of the ER or mitochondria, a previously unknown membrane source, the ER–Golgi intermediate compartment (ERGIC), was most actively triggering LC3 lipidation. Now, my new lab at Tsinghua still works on how the ERGIC controls autophagosome biogenesis under physiological and pathological conditions.
How does this finding fit with studies that have proposed other membrane sources for autophagosome formation?
Indeed, there have been several membrane origins indicated in the field, including the ER, mitochondrial membranes, the Golgi or even lipid droplets. So, I'm not going to say that the ERGIC is the best membrane source, we rather think it could be the selected membrane source based on the cell type, and we do find that in some cell types the ERGIC is important, while in others it is not.
Beyond these aspects of autophagy, what other scientific questions are you trying to answer with your lab?
In general, we want to understand how cellular membranes are remodelled structurally and functionally to cope with stress. Apart from autophagy, our lab is investigating unconventional protein secretion (UPS), which is also induced by stress conditions. Unlike classical secretion, where proteins with a peptide signal traffic through the ER and Golgi, in UPS the proteins without a signal peptide are released independently of the traditional ER–Golgi trafficking pathway. An important question is how UPS cargoes enter membrane trafficking pathways, and we recently identified a protein translocation process termed TMED10-channelled UPS (THU), through which multiple UPS cargoes enter the ERGIC. Interestingly, this is convergent with the finding from my postdoc that the ERGIC contributes to autophagosome biogenesis, and it implies that autophagy also performs unconventional secretory functions beyond degradation. We are currently working on the mechanism of THU, as well as how the ERGIC coordinates secretion and autophagy.
What challenges did you face when starting your own lab that you didn't expect?
Things were going smoothly, thanks to the School of Life Sciences at Tsinghua University's established system to nurture young PIs, until the beginning of 2020 and the COVID-19 outbreak. Then, the lab was shut down for half a year, and so several projects stopped progressing. This was really a difficult time for both me and the students, but to cope with the anxiety and to do something productive, our lab organised online journal club seminars twice a week, which also attracted many students from outside of our lab.
What elements, inside or outside the lab, have been key to your success so far?
There is still a long way to go until I consider myself successful, but as I mentioned, the School of Life Sciences at Tsinghua University has a terrific mentoring system to support young investigators, and I received a lot of help from two senior PIs, Dr Li Yu and Dr Ye-Guang Chen, in preparing grant applications and running projects. Also, the National Natural Science Foundation of China (NSFC) launched a special funding program for organelle research, and through this, cell biologists throughout the country formed a community for scientific discussion and collaboration, and they also generously share reagents and ideas. Inside the lab, I highly appreciate my students and postdocs who work hard on their projects. And I'm especially thankful to my wife, Dr Min Zhang, who is also a former postdoc in the Schekman lab. She sacrificed her career to join my lab as a senior scientist to push forward projects and help me to train junior lab members. Fortunately, she will become a PI in the coming year and progress her own scientific career.
What characteristics do you look for when recruiting new group members?
We have a programme of two-month rotations for students, and during that time I get a chance to know their personality, interests, experimental skills and work ethic. We always welcome open-minded, responsible and collaborative students, and on top of that we will pick those who are highly motivated and creative. I encourage the new students joining our lab to spend one year working on something they dreamt of when choosing biology as their major, or to try some crazy ideas in cell biology that don't need to be related to the ongoing projects of the lab.
“I encourage the new students joining our lab to spend one year working on something they dreamt of when choosing biology as their major, or to try some crazy ideas in cell biology that don't need to be related to the ongoing projects of the lab.”
That's interesting, I've so far mainly heard about such practices at very established research labs…
We actually only started doing this after the first three years – so once we published and got some grants, the lab settled down a bit and we had more students joining. After three years, I realised we need people to try new things that I've never thought about doing before, so that's why I recently changed our strategy.
What is the best science-related advice you ever received?
The advice that I benefited from most is ‘be brave to pursue your curiosity’ – and following my curiosity has really been my major motivation to do scientific research. In addition, what I have found successful scientists to have in common is that they are open-minded, generous and supportive, which are important characteristics for young PIs to develop in order to be good mentors.
“[…] what I have found successful scientists to have in common is that they are open-minded, generous and supportive, which are important characteristics for young PIs to develop in order to be good mentors.”
Could you tell us an interesting fact about yourself that people wouldn't know by looking at your CV?
I used to have a lot of hobbies when I was young, including different sports, music and chess. As I grew older, I only kept basketball and piano. In our school we have a weekly basketball game for students and faculty members, which is a good opportunity to exercise and make new friends. As for the music part, I spend some of my time after work playing the piano and have completed some masterpieces that I dreamt of playing when I was young, such as the Beethoven Sonatas – Pathétique, Moonlight and Appassionata.
Liang Ge's contact details: Tsinghua University, 100084 Beijing, China.
Liang Ge was interviewed by Máté Pálfy, Features & Reviews Editor at Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.