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Cell type-selective secretome profiling in vivo.

ABSTRACT: Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte and myeloid cell secretomes by direct purification of biotinylated secreted proteins from blood plasma. Our secretome dataset validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by the increased unconventional secretion of the cytosolic enzyme betaine-homocysteine S-methyltransferase (BHMT). This secretome profiling strategy enables dynamic and cell type-specific dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

SUBMITTER: Wei W

PROVIDER: S-EPMC7904581 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cell type-selective secretome profiling in vivo

Project description:Secreted polypeptides are a fundamental biochemical axis of intercellular and endocrine communication. However, a global understanding of composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection, and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte, and myeloid cell secretomes by direct purification of biotinylated secreted polypeptides from blood. Our secretome dataset validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types, and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by increased unconventional secretion of the cytosolic enzyme BHMT. This secretome profiling strategy enables dynamic and cell-type dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

2020-12-07 | PXD021602 | Pride

Eavesdropping on altered cell-to-cell signaling in cancer by secretome profiling.

Project description:In the past decade, cumulative clinical experiences with molecular targeted therapies and immunotherapies for cancer have promoted a shift in our conceptual understanding of cancer. This view shifted from viewing solid tumors as a homogeneous mass of malignant cells to viewing tumors as heterogeneous structures that are dynamically shaped by intercellular interactions among the variety of stromal, immune, and malignant cells present within the tumor microenvironment. As in any dynamic system, identifying how cells communicate to maintain homeostasis and how this communication is altered during oncogenesis are key hurdles for developing therapies to restore normal tissue homeostasis. Here, I discuss tissues as dynamic systems, using the mammary gland as an example, and the evolutionary concepts applied to oncogenesis. Drawing from these concepts, I present 2 competing hypotheses for how intercellular communication might be altered during oncogenesis. As an initial test of these competing hypotheses, a recent secretome comparison between normal human mammary and HER2+ breast cancer cell lines suggested that the particular proteins secreted by the malignant cells reflect a convergent evolutionary path associated with oncogenesis in a specific anatomical niche, despite arising in different individuals. Overall, this study illustrates the emerging power of secretome proteomics to probe, in an unbiased way, how intercellular communication changes during oncogenesis.

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Quantitative proteomics establishes the cell type-resolved mouse brain secretome

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Identification of a Novel <i>Salmonella</i> Type III Effector by Quantitative Secretome Profiling.

Project description:Salmonella enterica serovar Typhimurium is arguably one of the most studied bacterial pathogens and successful infection requires the delivery of its virulence factors (effectors) directly into host cells via the type III secretion systems (T3SSs). Central to Salmonella pathogenesis, these effector proteins have been subjected to extensive studies over the years. Nevertheless, whether additional effectors exist remains unclear. Here we report the identification of a novel Salmonella T3SS effector STM1239 (which we renamed SopF) via quantitative secretome profiling. Immunoblotting and β-lactamase reporter assays confirmed the secretion and translocation of SopF in a T3SS-dependent manner. Moreover, ectopic expression of SopF caused significant toxicity in yeast cells. Importantly, genetic ablation of sopF led to Salmonella strains defective in intracellular replication within macrophages and the mutant were also markedly attenuated in a mouse model of infection. Our study underscores the use of quantitative secretome profiling in identifying novel virulence factors for bacterial pathogens.

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Cell type-specific ribosome profiling in vivo.

Project description:Cell type-specific ribosome profiling in vivo.

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Chromatin state changes during neural development revealed by in vivo cell-type specific profiling.

Project description:A key question in developmental biology is how cellular differentiation is controlled during development. While transitions between trithorax-group (TrxG) and polycomb-group (PcG) chromatin states are vital for the differentiation of ES cells to multipotent stem cells, little is known regarding the role of chromatin states during development of the brain. Here we show that large-scale chromatin remodelling occurs during Drosophila neural development. We demonstrate that the majority of genes activated during neuronal differentiation are silent in neural stem cells (NSCs) and occupy black chromatin and a TrxG-repressive state. In neurons, almost all key NSC genes are switched off via HP1-mediated repression. PcG-mediated repression does not play a significant role in regulating these genes, but instead regulates lineage-specific transcription factors that control spatial and temporal patterning in the brain. Combined, our data suggest that forms of chromatin other than canonical PcG/TrxG transitions take over key roles during neural development.

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Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models.

Project description:Challenges in demonstrating durable clinical responses to molecular-targeted therapies have sparked a re-emergence in viewing cancer as an evolutionary process. In somatic evolution, cellular variants are introduced through a random process of somatic mutation and are selected for improved fitness through a competition for survival. In contrast to Darwinian evolution, cellular variants that are retained may directly alter the fitness competition. If cell-to-cell communication is important for selection, the biochemical cues secreted by malignant cells that emerge should be altered to bias this fitness competition. To test this hypothesis, we compared the proteins secreted in vitro by two human HER2+ breast cancer cell lines (BT474 and SKBR3) relative to a normal human mammary epithelial cell line (184A1) using a proteomics workflow that leveraged two-dimensional gel electrophoresis (2DE) and MALDI-TOF mass spectrometry. Supported by the 2DE secretome maps and identified proteins, the two breast cancer cell lines exhibited secretome profiles that were similar to each other and, yet, were distinct from the 184A1 secretome. Using protein-protein interaction and pathway inference tools for functional annotation, the results suggest that all three cell lines secrete exosomes, as confirmed by scanning electron microscopy. Interestingly, the HER2+ breast cancer cell line exosomes are enriched in proteins involved in antigen-processing and presentation and glycolytic metabolism. These pathways are associated with two of the emerging hallmarks of cancer: evasion of tumor immunosurveillance and deregulating cellular energetics.

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