Autophagosome biogenesis: synergistic remodeling of the endomembrane system
Liang Ge, Ph.D. (Research Specialist)
Randy Schekman lab, Department of Molecular and Cell Biology, University of California, Berkeley
Autophagy is a fundamental cellular process for bulk turnover of cytoplasmic components through
lysosomal degradation. The basic role of autophagy is to maintain cellular homeostasis as well as to
promote survival under stress conditions. Dysfunctional autophagy is tightly related to aging and many
human disorders such as cancer, neurodegeneration and metabolic syndromes. A key step of autophagy
is the formation of double-membrane vesicles, termed autophagosomes, which is built upon a significant
membrane contribution from the endomembrane system. The identity of the membrane compartment
supplying autophagosome biogenesis and the mechanism underlying the process of membrane
contribution are longstanding questions in the autophagy research field. To answer these questions, I
established a biochemical approach to reconstitute an early step of autophagosome biogenesis in a
cell-free reaction. In combination with membrane fractionation, I identified the ER-Golgi intermediate
compartment (ERGIC), a sorting station between the ER and Golgi, as the compartment supplying
membrane for an essential step of autophagosome biogenesis. Using super-resolution imaging, I found
that a synergistic remodeling of the ER-exit sites and the ERGIC generates the early autophagosome
precursors, which is achieved through a coordinated action of the autophagic phosphatidylinositol-3
kinase complex and the COPII membrane remodeling machinery. In summary, my study reveals a
mechanism accounting for the membrane supply for autophagosome biogenesis, therefore providing a
foundation for targeting autophagy for therapeutic purposes.
Biography
Dr. Ge’s passion for science and curiosity about living creatures came from his father, a professor who is
devoted to his career and loves nature. Dr. Ge embarked on his scientific career doing graduate study at
the Institute of Biochemistry and Cell Biology, one of the top research institutes in China. His work was to
decode the molecular mechanism of enterohepatic cholesterol absorption. Dr. Ge focused on a protein
essential for cholesterol absorption, called Niemann-Pick C1-Like 1 (NPC1L1). He established a
cell-based assay to determine NPC1L1-mediated cholesterol uptake. Combining this assay with
proteomics, biochemical fractionation, and a mouse model, Dr. Ge found that NPC1L1 mediates
cholesterol update by forming cholesterol-enriched membrane microdomains and clathrin-mediated
endocytosis. Further, he discovered that the hypocholesterolemic drug ezetimibe (Zetia) acts by inhibiting
the formation of cholesterol-enriched microdomains, thereby inhibiting cholesterol absorption. His work
reveals the mechanism of cholesterol absorption and provides a way to screen for novel cholesterol
absorption inhibitors. The work was presented in four publications in the journal of Cell Metabolism, PNAS,
and JBC, and led to one patent and one research grant. Dr. Ge was also honored with several national or
international awards, including a FEBS travel grant and the Wang Yinglai Scholarship named after Yinglai
Wang, the first scientist in the world to engineer synthetic insulin.
During these studies, Dr. Ge was fascinated by the interesting features of membrane transport. After
graduation, he continued his scientific career as a post-doctoral fellow working on an essential catabolic
cellular process called autophagy under the mentorship of Dr. Randy Schekman at the University of
California, Berkeley. Autophagosomes, the organelles for autophagy, greatly aroused his interest. It has a
unique double-membrane structure, and the biogenesis of the autophagosome remains largely unknown.
His project was to learn the membrane origin of the autophagosome, which has puzzled the field for
decades due to the lack of a proper assay to directly link a membrane source to autophagosome
biogenesis. To solve this puzzle, Dr. Ge established a cell-free assay to biochemically reconstitute
autophagosome biogenesis and a systematic membrane fractionation technique. Combination of the two
approaches allowed him to identify the ER-Golgi intermediate compartment (ERGIC) as a membrane
origin of the autophagosome. Dr. Ge then employed the unique system he established to dissect the
mechanism of how the ERGIC generates membranes for the autophagosome. In combination with
super-resolution microscopy, he identified a pathway including the ER-exit site, the ERGIC, and the COPII
machinery for vesicle trafficking which supplies membranes for the growth of the autophagosome. The
work was presented in three research papers (two published in eLife and one in submission) and four
review articles. During his postdoctoral period, Dr. Ge was awarded a Human Frontier Science Program
Fellowship and a Jane Coffin Childs Fellowship. Recently, Dr. Ge successfully obtained the NIH Pathway
to Independence Award (K99/R00) to support his current and future independent work.
Dr. Ge’s research goal is to employ basic research to understand the fundamental questions related to
neurodegenerative diseases. Dr. Ge’s career goal is to become an independent scientist and excellent
mentor to work for the benefit of human health and nurture the next generation of young scientists.