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Results for “phospho-proteomics”

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PubMed2025

Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.

Loss-of-function variants in TBK1, encoding a protein kinase, are strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how haploinsufficiency for TBK1 leads to age-related neurodegeneration remains unresolved. Here, we utilize sets of isogenic induced pluripotent stem cells (iPSCs) with loss of TBK1 or loss of optineurin (OPTN) for quantitative global proteomics and phospho-proteomics in both stem cells and excitatory neurons. We found that TBK1 sustains the abundance and phosphorylation of its interacting adapter proteins, AZI2/NAP1, TANK, and TBKBP1/SINTBAD. Moreover, TBK1 regulates the phosphorylation of endo-lysosomal proteins, such as GABARAPL2, the late-endosome GTPase RAB7A, and selective autophagy cargo receptor proteins-including novel phospho-sites in p62/SQSTM1-in neurons. Finally, we provide a census of the phospho-proteome in nascent human neurons for further studies. Overall, TBK1 serves as a point of convergence in ALS/FTD-linked endo-lysosomal networks that act in a cell-autonomous manner to maintain protein homeostasis in neurons.

Humans↗

PubMed2025

Analytical Considerations for the Development of Plate-Based Proteomics Platforms Using Isobaric Labeling.

Mass spectrometer-based proteomics platforms have great potential to rapidly advance our systematic understanding of complex biological problems, enable drug discovery, decipher drug mechanisms of action, and discover novel biomarkers. As the demand for processing large sets of samples in an automatic manner is constantly increasing, the integration of automation platforms (nanoliter dispensers, liquid handlers, etc.) has become a routinary configuration paired with liquid chromatography-mass spectrometers. The functional integration of all of those instruments into a single unit is what we call a plate-based high-throughput proteomics platform (HT proteomics). The readout of the platform is the quantitative proteome data at the protein or peptide level. In this work, we developed a plate-based HT proteomics standard that we called the HT-sKO. The HT-sKO allows the evaluation of accuracy and the estimation of the relative limit of quantification when the target proteins vary up to 60-fold in abundance. The HT-sKO utilizes nonhuman recombinant proteins that can be spiked into the samples, allowing for sample acquisition and HT proteomics platform evaluation at the same time. We also showed the foundational role of a robust acquisition strategy for developing a stable HT proteomics platform and the value of using a tube-based method as an informant assay on data quality expectations for the platform. Using this new standard, we demonstrated that the intra- and inter-plate variance is around 4-6% for the protein level or around 10% for the peptide-level readout. We also showed that the HT-sKO standard is compatible with whole-proteome, phospho-proteome, and reactive cysteine profiling platforms.

Proteomics↗

PubMed2026

Selective Enrichment of Newly Synthesized Proteins Using Phos-Tag Click Tip Enables Nascent Proteome Analysis in Influenza A Virus Infection.

Profiling of newly synthesized proteins (NSPs) provides access to dynamic changes in protein production that accompany acute cellular responses. Bioorthogonal noncanonical amino acid tagging (BONCAT)-based approaches enable selective labeling of NSPs; however, their broader application remains constrained by labor-intensive enrichment workflows and limited sensitivity for direct peptide-level analysis. Here, we developed a workflow termed "Phos-tag Click Tip" by integrating a phosphorylated variant of bicyclononyne (pBCN) with Phos-tag affinity purification to selectively capture azidohomoalanine (AHA)-labeled peptides for newly synthesized proteome analysis (NSProteomics). This approach overcomes key limitations of conventional proteomics and BONCAT-based strategies by enabling efficient enrichment and sensitive detection of NSP-derived peptides. Using this workflow, we performed comprehensive NSP profiling of host cells during influenza A virus infection. We identified dynamic changes in distinct NSP profiles associated with viral replication, host restriction, and immune responses, many of which were not readily detected with conventional whole-cell- or phospho-proteomic analyses. Overall, the Phos-tag Click Tip workflow provides a complementary approach for stimulus-responsive NSP profiling, offering functionally relevant insights into host-virus interactions and cellular response mechanisms.

Proteome↗

PubMed2026

BRIDGE: an interactive application for multi-omics data analysis, visualization and integration.

SUMMARY: BRIDGE is a Shiny-based application that provides an accessible, modular platform for individual and integrative multi-omics analysis. Using an independent SQLite database backend, it offers a local, private, and user-friendly environment that requires no prior computational expertise. The application supports proteomics, phospho-proteomics, and RNA-seq analyses through a comprehensive suite of visualization and analytical modules, together with an integrated multi-omics analysis pipeline. Built-in caching and asynchronous processing improve responsiveness, enabling efficient exploration, analysis, and visualization of multi-omics datasets on moderate hardware. AVAILABILITY AND IMPLEMENTATION: BRIDGE is implemented in R using Shiny and is freely available as a Docker container at https://ghcr.io/paulilab/bridge. A public demonstration server with example datasets is available at https://bridge.imp.ac.at. Code and datasets are also available at https://github.com/paulilab/BRIDGE and under DOI: https://doi.org/10.5281/zenodo.20215824.

Multiomics↗

PubMed2026

Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma.

The progression of multiple myeloma (MM), an incurable malignancy of plasma cells, is often associated with the suppression of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. The mechanisms underlying this suppression remain largely unknown. Here, we identified serine/threonine kinase 17b (STK17B) kinase as a critical suppressor of ferroptosis in MM. Elevated levels of STK17B are associated with poor overall survival in patients with MM, and STK17B expression is significantly higher in relapsed vs newly diagnosed MM cases. We found that inhibiting STK17B in MM cells increased the labile iron pool, enhanced lipid peroxidation, and sensitized cells to conventional anti-MM therapies. Notably, an orally available, in-house-generated STK17B inhibitor induced ferroptosis and significantly reduced tumor growth in MM xenograft mouse models. Mechanistically, proximity labeling assay combined with the phospho-proteomic analysis identified 2 major regulators of iron uptake and transport as direct targets of STK17B: iron-responsive element binding protein 2 (IREB2), and heat shock protein family B member 1 (HSPB1). We demonstrated that STK17B phosphorylates critical regulatory sites on IREB2 (S157) and HSPB1 (S15), thereby modulating the balance between IREB2 and HSPB1 downstream effectors, proferroptotic transferrin receptor, and antiferroptotic ferritin heavy chain proteins. Furthermore, we demonstrated that STK17B indirectly maintains activating phosphorylation of STAT3, a ferroptosis suppressor and a major driver of MM pathobiology. Our findings uncovered a clinically relevant and targetable STK17B-pIREB2S157/pHSPB1S15 signaling axis that suppresses ferroptosis and contributes to drug resistance in MM.

Ferroptosis↗