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Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics

ABSTRACT: Proteomics is making important contributions to drug discovery - from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here, we introduce decryptE, a proteome-wide approach that measures the full dose-response characteristics of drug-induced protein expression changes which informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in >1 million dose-response curves that can be interactively explored online in ProteomicsDB and a custom-built ShinyApp. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered novel aspects of the MoAs of human medicines. Most notable, HDAC inhibitors potently and strongly down-regulated the T-cell receptor complex resulting in impaired human T-cell activation in-vitro and ex-vivo. This not only offers a rational explanation for the efficacy of HDAC inhibitors in certain lymphomas and autoimmune diseases but also their poor performance in treating solid tumors.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Exploris 480

ORGANISM(S): Pseudomonas Aeruginosa (ncbitaxon:287) Arabidopsis Thaliana (ncbitaxon:3702) Escherichia Coli (ncbitaxon:562) Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Bernhard Kuster

PROVIDER: MSV000093659 | MassIVE | Wed Dec 13 12:34:00 GMT 2023

SECONDARY ACCESSION(S): PXD047799

REPOSITORIES: MassIVE

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Project description:Sensing of microbial products by innate immune cells skew their transcriptional program to optimize anti-microbial defences. Chromatin remodeling by histone deacetylases (HDACs) plays a fundamental role in tailoring gene expression. HDAC inhibitors are among the most promising anti-cancer drugs and possess intrinsic anti-inflammatory properties. Yet, the influence of HDAC inhibition on innate immune responses to microbial infection is unknown. Here we show that HDAC inhibitors repress the expression of less than 10% of the genes expressed at baseline in BM-derived macrophages. In sharp contrast, HDAC inhibitors strongly interfere with transcriptome remodeling induced by LPS and Pam3CSK4, affecting the expression of 30-70% of genes modulated by microbial stimuli. Strikingly, HDAC inhibitors target the expression of numerous genes involved in anti-microbial host defences, encoding for microbial sensors, cytokines, chemokines, growth factors and their receptors, adhesion and signaling molecules, and molecules involved in antigen processing and presentation. At the molecular level, HDAC inhibitors do not impair mitogen-activated protein kinase, NF-kB, interferon-related factor signal and STAT1 transduction pathways, but inhibit NF-kB p65 recruitment to the promoter region of HDAC inhibitor-sensitive genes. HDAC inhibitors also inhibit the response of mouse and human DCs, splenocytes and whole blood to a broad range of microbial products and microorganisms. In agreement with these in vitro findings, HDAC inhibitors increase bacterial burden and sensitize mice to sub-lethal infection with Klebsiella pneumoniae and Candida albicans. Conversely, HDAC inhibitors confer protection in models of Pam3CSK4-induced fulminant toxic shock and severe sepsis following cecal ligation and puncture. Overall, these data substantiate the concept of immunomodulation by HDAC inhibitors, and suggest that these drugs could represent efficacious adjunctive therapy of severe sepsis. Mus musculus cells were grown in presence of LPS or LPS + TSA and pam or pam + TSA and hybrydised against a cRNA pool UMRR (from Mus musculus cells).

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Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics

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