Ying Lu, 2023, 2025
Who he is
Ying Lu, Ph. D. is an Assistant Professor in the Department of Systems Biology, Harvard Medical School. He received an undergraduate degree in physics from Peking University in China, before moving to The Rockefeller University to work with Dr. Frederick Cross on cell cycle regulation, where he received a Ph.D degree there in biophysics in 2010. He was a postdoctoral fellow with Dr. Marc Kirschner in the department of Systems Biology. There, he developed single-molecule microscopy methods to investigate the process of protein ubiquitylation and degradation, and led several structural studies on the human 26S and 19S proteasomes. Dr. Lu was appointed assistant professor in 2017.
What he does
The protein degradation system is at the center of cellular protein homeostasis and is closely associated with many human pathologies. The mechanism by which the degradation system selects its targets and effectively degrades them has not been well understood. Dr. Lu’s group develops interdisciplinary methods and endeavors to understand how the key degradation machinery, namely the proteasome and the p97/VCP complex, operates and how a failure to degrade protein may cause diseases.
The lab has two current areas of focus:
1. Structural dynamics of the 26S proteasome. Intricate changes of the proteasome’s conformation underlie most of its activities and has been challenging to study by most experimental methods. We pioneered the empirical free-energy landscape approach to simulate the global conformational dynamics of the proteasome, for addressing the key questions in protein degradation.
2. Clearance of challenging protein substrates. While the canonical pathways of proteasomal and autophagic degradation are well documented, the mechanisms by which cells eliminate “difficult” substrates—such as structurally stable proteins, certain membrane factors, protein complexes, and aggregates—remain poorly understood. These substrates may resist conventional degradation processes and likely require additional factors or specialized steps for efficient clearance. Failure to effectively remove such targets can disrupt cell physiology and contribute to disease pathogenesis. Our objective is to identify the key regulators and elucidate the molecular mechanisms governing the clearance of these challenging substrates, thereby uncovering their biological significance.
News from the Lab
Ubiquitin Signal Amplification. In a search for unknown factors required for degrading difficult substrates, we discovered that HUWE1, a HECT-family E3, can broadly stimulate the degradation of soluble factors, including many therapeutic targets, and protein aggregates. We found that HUWE1 promotes degradation through rapidly expanding the ubiquitin modification on its targets that have already been ubiquitylated, using a novel “ubiquitin-directed ubiquitin ligase” activity. The expanded ubiquitin modification recruits the p97/VCP unfoldase to promote the clearance of these targets.
The size filter in aggresome formation. The cell mitigates the toxicity of misfolded and aggregated proteins by sequestering them into a perinuclear structure known as the aggresome, through dynein-mediated transport. We discovered that aggresome formation is controlled by a “size filter” that preferentially targets large aggregates for sequestration. By reconstituting aggresome formation in a cell-free system, we observed that protein aggregates engage in transient, yet recurrent, interactions with the dynein motor. This cyclical on/off engagement creates a size-dependent bias, favoring the transport of larger aggregates and offsetting the increased viscous drag associated with their size. Our findings provide insight into how small aggregates may evade cellular quality control, potentially contributing to their accumulation in protein aggregation disorders.
