Yansheng Liu, PhD

Specific Research Areas

Proteostasis, or protein turnover, is a fundamental process that balances protein production and degradation. Our research aims to uncover how proteostasis and post-translational modifications (PTMs) shape cellular function and how their dysregulation drives human diseases.

1. Impact of protein PTMs on proteostasis.

Protein PTMs, such as phosphorylation, profoundly influence protein turnover; however, this relationship remains underexplored. We developed the DeltaSILAC MS method to quantify how thousands of phosphosites affect turnover and discovered that phosphorylation often slows degradation, a trend underappreciated in earlier studies (Developmental Cell, 2021). Recently, we profiled turnover rates for 11,000 proteins and ~40,000 phosphosites across eight mouse tissues and brain regions, identifying tissue-specific patterns and phosphosites that stabilize neurodegeneration-linked proteins such as Tau, for which chemical approaches like PhosTACs hold promise to reverse (Cell, 2025).

2. Impact of chromosome aneuploidy on proteostasis in cancer and genetic diseases.

Building on our Cell review on proteomic buffering (Cell, 2016) and postdoctoral work on trisomy 21, we uncovered striking proteomic heterogeneity in aneuploid HeLa cells. We showed that “gain-type” aneuploidies stabilize protein complex stoichiometry via selective degradation. Excitingly, we recently demonstrated that “loss-type” aneuploidies employ selective synthesis to maintain balance, enabling tolerance to Chromosome 3 arm loss prevalent in lung cancer (Molecular Cell, 2025). We have also contributed to other work on aneuploidy (Science, 2023). We are now investigating how disease aneuploidy alters proteostasis and phosphorylation to produce “on/off-target” activities.

3. Dynamics and stability of phosphorylation networks.

To define phosphoproteomic regulatory mechanisms, we have (a) shown that temporal patterns, not just stimulation magnitude, shape Akt signaling (Nature Communications, 2023); (b) elaborated on mechanisms of action for temporal treatment of colon cancer drugs (Nature Communications, 2024); and (c) mapped conserved phosphorylation networks and motifs across mammalian species (Cell Reports Methods, 2024; Science Advances 2022).

4. Development of DIA-MS techniques and bioinformatic tools for PTM and proteostasis analysis.

We continue to advance the applicability of DIA-MS by developing new techniques, such as RTwinDIA and BoxCarmax-DIA (Analytical Chemistry 2021). We have also developed software such as NAguideR (Nucleic Acids Research, 2020) for missing-value imputation and ISW/KdeggeR for turnover analysis (Nature Communications, 2025; Molecular Systems Biology, 2020).

Collaborations at Yale and Outlook.

We collaborate extensively with Yale groups on lung, breast, and pancreatic cancers, as well as SARS-CoV-2. Through integrated lipidomic-proteomic research and strong departmental & YSM support, we have recently installed a state-of-the-art MALDI imaging MS and have begun to further advance our understanding of how lipids, PTMs, and proteostasis are altered at the single-cell, spatial, and clinical levels.