Ribosome Newsletter: Navigating the Convergence of Proteomics, AI, Synthetic Biology, and Translational Medicine

Welcome to this week's edition of the Ribosome! This week, we explore studies on proteome dynamics under stress, the development of zinc-finger degrons for protein degradation, and the identification of therapeutic targets in colorectal and breast cancer. We also delve into the potential of circRNA-derived peptides for cancer immunotherapy. Join us for these insights into the latest advancements in proteomics and their implications for translational medicine.

Proteomics Innovations

Proteome Dynamics Disrupted by ER Stress and Drug Response

This study introduces a mass spectrometry-based proteomics strategy called Simultaneous Proteome Localization and Turnover (SPLAT) to simultaneously measure protein turnover rates and subcellular localization. Applying SPLAT to human AC16 cardiac cells and iPSC-derived cardiomyocytes under ER stress, the researchers found that the unfolded protein response (UPR) differentially affects protein turnover based on subcellular location, with a proteome-wide slowdown but acceleration among stress response proteins in the ER and Golgi. Additionally, UPR triggers broad differential localization of proteins, including RNA-binding proteins and amino acid transporters. The study also applied SPLAT to explore the mechanism of cardiotoxicity in iPSC-derived cardiomyocytes treated with the proteasome inhibitor carfilzomib, revealing that carfilzomib selectively disrupts sarcomere protein homeostasis. This research provides insights into the interactions of protein spatial and temporal dynamics and demonstrates a method to examine protein homeostasis regulations in stress and drug response.

Evolution of Compact Zinc-Finger Degrons for Protein Degradation

Mercer et al. developed a phage-assisted continuous evolution platform to create compact zinc-finger degron tags that bind to the ubiquitin ligase substrate receptor cereblon in complex with PT-179, a thalidomide derivative without off-target effects. The evolved 36–amino acid degron, SD40, enables specific degradation of tagged endogenous proteins in human cells when treated with PT-179. This system offers a new approach for conditional protein degradation and provides insights into the molecular basis of SD40's activity and specificity.

Therapeutic Applications

Deep Proteomic Characterization of Colorectal Cancer Subtypes

This study delves into the proteomic landscape of colorectal cancer (CRC) subtypes defined by the Consensus Molecular Subtypes (CMS) framework. By analyzing 158 stage II-III colon cancer samples using data-independent acquisition mass-spectrometry proteomics, the research uncovers distinct protein expression profiles for each CMS. CMS1 exhibits overexpression of immune-related proteins and a glycolytic profile, suggesting potential for immunotherapy and glycolytic inhibitors. CMS2 is heterogeneous, with two proteomic subtypes identified, each with different prognostic implications. CMS3 shows metabolic protein overexpression, while CMS4 is characterized by proteins related to angiogenesis, extracellular matrix, and possible chemoresistance, correlating with a higher metastatic profile and worse prognosis. These findings provide a deeper understanding of CRC subtypes and highlight potential therapeutic targets for personalized treatment strategies.

Targeting PRMT5 in CDK4/6 Inhibitor-Resistant Breast Cancer

CDK4/6 inhibitors (CDK4/6i) have improved survival in estrogen receptor-positive (ER+) breast cancer, but resistance eventually develops, often due to RB1 loss-of-function. A genome-wide CRISPR screen identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB-deficient breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independently of RB, leading to growth arrest. Mechanistically, PRMT5 inhibition resulted in dissociation of fused in sarcoma (FUS) from RNA polymerase II, causing hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and downregulation of proteins involved in DNA synthesis. Dual blockade of ER and PRMT5 with the PRMT5 inhibitor pemrametostat and the selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts, highlighting a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

CircRNA-Derived Peptides in Cancer Immunotherapy

This study introduces an immunopeptidomics workflow focused on identifying peptides derived from circular RNAs (circRNAs) that are naturally presented by human leukocyte antigens (HLAs) and could serve as tumor-specific antigens for cancer immunotherapy. The workflow identifies 54 unique peptides encoded by circRNAs in melanoma and lung cancer samples, expanding the catalog of potential immunotherapy targets. The findings suggest that circRNA-derived peptides, especially those spanning the back-splice junction (BSJ), could be promising candidates for cancer immunotherapy, offering a novel avenue for targeting tumor cells.

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