Uncovering epiProteome Regulation in Health & Disease

Our lab explores how post-translational modifications and proteasome dynamics regulate cellular identity, immunity, and disease progression. Our recent studies have uncovered key molecular mechanisms shaping epigenetic and proteostatic landscapes in various biological contexts. 

In the context of early mammalian development, we revealed that SUMOylation of linker histone H1 plays a crucial role in maintaining chromatin compaction during the totipotency-to-pluripotency transition, preventing reactivation of the totipotency program in embryonic stem cells (Molecular Cell, Sheban et al., 2021). 

In cancer, we identified proteasome complex heterogeneity as a critical determinant of tumor-immune interactions. We found that upregulation of the proteasome regulator PSME4 drives immune evasion and is associated with resistance to immunotherapy by attenuating antigen presentation and T cell-mediated immunity (Nature Cancer, Javitt et al., 2023).

Additionally, we discovered a proteasome-dependent degradation pathway at the Golgi apparatus (GARD) that facilitates Golgi dispersal under stress, linking proteostasis to secretory organelle dynamics and offering a therapeutic target for multiple myeloma (Nature Communications, Eisenberg-Lerner et al., 2020). Finally, we uncovered a novel role for proteasomes in innate immunity, demonstrating that proteasome-derived peptides possess antimicrobial properties, providing an untapped source of natural antibiotics (Nature, Goldberg et al., 2025).

We were also the first to uncover the modified immunopeptidome landscape, in cancer. Using the Protein Modification Integrated Search Engine (Nature Biotech, Kacen et al., 2023), developed in our lab, we profiled post-translational modifications (PTMs) at scale across diverse biological samples. By integrating PTMs into proteomic data, PROMISE illuminates the "dark matter" of the proteome, revealing how these modifications regulate protein function. In the context of tumor immunology, we revealed novel principles of PTM-driven antigenicity. This approach enables us to expand our understanding of disease pathophysiology in cancer, autoimmunity, neurodegeneration, and more, providing new insights into protein regulation and potential therapeutic targets.

Through these discoveries, we aim to decode the epiProteomic regulation of cellular function, with implications for stem cell biology, cancer therapy, and immune defense.