Unlocking the mysteries of autophagy terminators
Chen’s second area of specialization is basic research related to ubiquitin.
As Chen explains, among the 76 amino acids in ubiquitin, there are eight “loci” (seven lysines—K6, K11, K27, K29, K33, K48, and K63—and methionine) that may serve as points for ubiquitination. When proteins are modified by the attachment of ubiquitin chains at different loci, they perform different functions.
For instance, K48-linked chains serve as proteolytic signals that target substrate proteins for degradation in proteasomes. Chen explores the functions of new ubiquitin chains, and was the first to discover the functions of proteins with K33-linked chains.
The third major area of research is related to autophagy, which is another mechanism for degrading and recycling cellular material. An example of this process, Chen says, is the way that under conditions of nutrient starvation, cells in the human body break down their own proteins and fats and convert them into energy. During the autophagy process, targeted constituents of the cytoplasm are isolated from the rest of the cell within a double-membraned vesicle called an autophagosome. The autophagosome then fuses with a lysosome and the contents are degraded and recycled.
Chen explains that the scientific community already knew that once initiated, autophagy within cells would increase in intensity for a time, but then would decline in intensity and eventually cease or “turn off.” But it was not known why the process would turn off, and it was her research that uncovered the mechanism by which autophagy is terminated.
“When cellular autophagy starts, several proteins are activated to form an autophagosome. When this protein complex is activated, KLHL20 is recruited to conduct ubiquitination, and the targeted material is gradually degraded.” Chen explains that KLHL20 plays a master role in the interplay between autophagy and the ubiquitin–proteasome system.
The reason this mechanism is important is that if autophagy does not turn off, it will lead to cell death. Using mouse models and cell-based studies, Chen and her team found that failure of autophagy termination also promotes muscle atrophy.
Chen says that it is already known that many diseases are connected to cellular autophagy. Some, such as the muscle atrophy produced by diabetes, are the result of excessive autophagy. Others are the result of insufficient autophagy. For example, Alzheimer’s disease is caused by buildup of proteins. “If we can suppress or strengthen the action of KLHL20, so that autophagy can continue uninterrupted or, alternatively, be turned off, then perhaps we can treat or cure these conditions.”
Using diabetic mouse models, Chen and her team found that failure of autophagy termination can lead to muscle atrophy.