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Human gut bacteria bioaccumulate per- and polyfluoroalkyl substances (PFAS), commonly known as forever chemicals, in intracellular aggregates. Colonization of gnotobiotic mice with bioaccumulating bacteria increases faecal PFAS excretion.

Here the authors present deep quantitative glycoprofiling (DQGlyco), a method that enables high-throughput analysis of protein glycosylation dynamics. Using DQGlyco, they link gut microbiome composition to brain glycoproteins and provide insights into glycoform functionality and tissue specificity.

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants.

Applying thermal proteome profiling to acute B cell childhood leukemia cell lines combined with deep peptide fractionation and a graph-based clustering algorithm allows inference of functional proteoform groups and their association with drug response.

ATP can function as a biological hydrotrope, but its global effects on protein solubility have not yet been characterized. Here, the authors quantify the effect of ATP on the thermal stability and solubility of the cellular proteome, providing insights into protein solubility regulation by ATP.

Nitroxoline is a bacteriostatic quinoline antibiotic, known to form complexes with metals, with few clinical applications. Here, Cacace et al. show that the compound displays a broad activity spectrum, with species-specific bactericidal activity, and acts as a metallophore inducing copper and zinc intoxication in bacterial cells.

Metabolic labeling is often used to measure protein turnover. Here the authors show that for interconvertible protein species like phosphoforms metabolic labeling does not provide information on turnover differences, but that the relative order of modification can determine the observed dynamics.

A combination of solubility proteome profiling with phosphoproteomics enables systematic analysis of the phosphorylation status of proteins in soluble and condensate-bound pools.

Unbiased proteome-level discovery of intracellular drug targets can be achieved by plotting melting curves of proteins from untreated and drug-treated cells. Multiplexed quantitative mass spectrometry using TMT10 reagents makes this possible.

The molecular mechanisms underlying resistance to therapy in Chronic lymphocytic leukemia (CLL) remain to be explored. Here, the authors perform multi-omics analysis in a mouse model of ibrutinib resistance and suggest proteasome inhibition for overcoming it.

A method for profiling changes in membrane protein thermal stability upon ligand binding using mass spectrometry identifies cellular membrane protein targets of small molecules.

2D-thermal proteome profiling (2D-TPP) is a powerful assay for probing interactions of proteins with small molecules in their native context. Here the authors provide a statistical method for false discovery rate controlled analysis for 2D-TPP applications.

Thermal proteome profiling combined with a reverse genetics approach provides insights into the abundance and thermal stability of the global proteome of Escherichia coli.

Phenotypic profiling of a phospho-deficient mutant library informs functional annotations of phosphosites.

The targets of small-molecule drugs are detected in tissue and blood using thermal proteome assays.

The proteome-wide characterization of proteostasis depends on robust approaches to determine protein half-lives. Here, the authors improve the accuracy and precision of mass spectrometry-based quantification, enabling reliable protein half-life determination in several non-dividing cell types.

d-arginine and d-lysine are chemorepellent molecules sensed by a novel chemotaxis receptor in Vibrio cholerae that trigger a run-away response under adverse conditions.

Using the proteome-wide pSILAC-AHA labelling approach, the authors resolve the host proteome spatiotemporal dynamics during macrophage infection with Salmonella enterica Typhimurium and reveal the active role of cathepsins in cell death via the non-canonical inflammasome.

Retron-Sen2 of Salmonella Typhimurium encodes a toxin and a reverse transcriptase, which, together with the Sen2 multi-copy single-stranded DNA synthesized by the reverse transcriptase make up a tripartite toxin–antitoxin system that functions in anti-phage defence.

A mass-spectrometry-based draft of the human proteome and a public database for analysis of proteome data are presented; assembled information is used to estimate the size of the protein-coding genome, to identify organ-specific proteins, proteins predicting drug resistance or sensitivity, and many translated long intergenic non-coding RNAs, and to reveal conserved control of protein abundance.

The meltome atlas compiles the thermal stability of 48,000 proteins across 13 species ranging from archaea to humans, providing a resource for analyzing protein stability in the context of function and interactions.

Pruning dendritic spines requires autophagy. Here, the authors show that autophagy is required for long-term depression (LTD), a major form of synaptic plasticity. LTD induces the biogenesis of autophagic vesicles locally in dendrites to facilitate the degradation of postsynaptic proteins.

A chemoproteomics approach utilizing the thermal shift assay and quantitative MS resulted in the identification of phenylalanine hydroxylase as an off-target of the histone deacetylase inhibitor panobinostat.

Cell surface thermal proteome profiling allows characterization of ligand-induced changes in protein abundances and thermal stabilities at the plasma membrane.

The substrate specificity of phosphoprotein phosphatases PP1 and PP2A depends on their catalytic and regulatory subunits. Using proteomics approaches, the authors here provide insights into the sequence specificity of the catalytic subunits and their distinct contributions to PP1 and PP2A selectivity.

An analysis of the interactions between 15 drugs and 25 gut bacterial strains shows that bioaccumulation of drugs within bacterial cells is another mechanism through which gut microorganisms can alter drug availability and efficacy.

Boos et al. show that impairing mitochondrial protein import induces a global transcriptional response to activate the ubiquitin–proteasome system and heat stress response and repress oxidative phosphorylation genes.​

Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.

Bantscheff et al. use chemoproteomics to measure the affinity of small molecules for megadalton protein complexes in cell extracts. Differences in the selectivity of HDAC inhibitors observed when native HDAC complexes are compared with their purified catalytic subunits suggest the limitations of using isolated recombinant proteins in certain drug screens.

A chemoproteomic approach adapted for high-throughput screening leads to the identification of a selective PI3Kγ inhibitor. Application of this inhibitor in human and mouse cellular models reveals a role for PI3Kγ in T_H17 cell differentiation.

Antibacterial combinations that are potent against Gram-positive bacteria are identified using an automated high-throughput screen.

Screening pairwise combinations of antibiotics and other drugs against three bacterial pathogens reveals that antagonistic and synergistic drug–drug interactions are specific to microbial species and strains.

Single-particle analysis of electron microscopy structures elucidates the mycobacterial ESX-5 type VII secretion system membrane complex.

Phosphorylation sites are ranked for functional relevance using a comprehensive, high-quality human phosphoproteome.

Here the authors summarize current knowledge of the regulation of protein stability by various post-translational modifications (PTMs) including methylation and phosphorylation. PTM-regulated degrons act as signals for protein degradation or stabilization.