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Physiological Reviews Jan 2020Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary... (Review)
Review
Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty acids (SCFAs) produced by gut microbial fermentation of the otherwise indigestible dietary fiber, constitute the major sources of free fatty acids (FFAs) in the metabolic network. Recently, increasing evidence indicates that FFAs serve not only as energy sources but also as natural ligands for a group of orphan G protein-coupled receptors (GPCRs) termed free fatty acid receptors (FFARs), essentially intertwining metabolism and immunity in multiple ways, such as via inflammation regulation and secretion of peptide hormones. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized. In particular, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain saturated and unsaturated fatty acids, while FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs, mainly acetate, butyrate, and propionate. In this review, we discuss the recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses. We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.
Topics: Animals; Fatty Acids, Nonesterified; Humans; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31487233
DOI: 10.1152/physrev.00041.2018 -
Neuron Dec 2022Cell-surface proteins (CSPs) mediate intercellular communication throughout the lives of multicellular organisms. However, there are no generalizable methods for...
Cell-surface proteins (CSPs) mediate intercellular communication throughout the lives of multicellular organisms. However, there are no generalizable methods for quantitative CSP profiling in specific cell types in vertebrate tissues. Here, we present in situ cell-surface proteome extraction by extracellular labeling (iPEEL), a proximity labeling method in mice that enables spatiotemporally precise labeling of cell-surface proteomes in a cell-type-specific environment in native tissues for discovery proteomics. Applying iPEEL to developing and mature cerebellar Purkinje cells revealed differential enrichment in CSPs with post-translational protein processing and synaptic functions in the developing and mature cell-surface proteomes, respectively. A proteome-instructed in vivo loss-of-function screen identified a critical, multifaceted role for Armh4 in Purkinje cell dendrite morphogenesis. Armh4 overexpression also disrupts dendrite morphogenesis; this effect requires its conserved cytoplasmic domain and is augmented by disrupting its endocytosis. Our results highlight the utility of CSP profiling in native mammalian tissues for identifying regulators of cell-surface signaling.
Topics: Mice; Animals; Proteomics; Mammals
PubMed: 36220098
DOI: 10.1016/j.neuron.2022.09.025 -
Physiological Research Sep 2020Ageing is accompanied by deterioration in physical condition and a number of physiological processes and thus a higher risk of a range of diseases and disorders. In... (Review)
Review
Ageing is accompanied by deterioration in physical condition and a number of physiological processes and thus a higher risk of a range of diseases and disorders. In particular, we focused on the changes associated with aging, especially the role of small molecules, their role in physiological and pathophysiological processes and potential treatment options. Our previously published results and data from other authors lead to the conclusion that these unwanted changes are mainly linked to the hypothalamic-pituitary-adrenal axis can be slowed down, stopped, or in some cases even reversed by an appropriate treatment, but especially by a life-management adjustment.
Topics: Aging; Animals; Hormones; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Receptors, Cell Surface; Small Molecule Libraries
PubMed: 33094624
DOI: 10.33549/physiolres.934523 -
Nature Oct 2022Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins...
Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras (PROTACs), have highlighted clinically important advantages of target degradation over inhibition. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for 'on-demand' degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.
Topics: Animals; Antibodies; Antibody Specificity; Colorectal Neoplasms; Ligands; Membrane Proteins; Proteolysis; Receptors, Cell Surface; Substrate Specificity; Ubiquitin-Protein Ligases
PubMed: 36131013
DOI: 10.1038/s41586-022-05235-6 -
Annual Review of Genomics and Human... Aug 2023The subcellular localization of a biopolymer often informs its function. RNA is traditionally confined to the cytosolic and nuclear spaces, where it plays critical and... (Review)
Review
The subcellular localization of a biopolymer often informs its function. RNA is traditionally confined to the cytosolic and nuclear spaces, where it plays critical and conserved roles across nearly all biochemical processes. Our recent observation of cell surface glycoRNAs may further explain the extracellular role of RNA. While cellular membranes are efficient gatekeepers of charged polymers such as RNAs, a large body of research has demonstrated the accumulation of specific RNA species outside of the cell, termed extracellular RNAs (exRNAs). Across various species and forms of life, protein pores have evolved to transport RNA across membranes, thus providing a mechanistic path for exRNAs to achieve their extracellular topology. Here, we review types of exRNAs and the pores capable of RNA transport to provide a logical and testable path toward understanding the biogenesis and regulation of cell surface glycoRNAs.
Topics: Humans; RNA; Cell Membrane; Membranes; Cytosol; Polymers
PubMed: 37068783
DOI: 10.1146/annurev-genom-101722-101224 -
Cell Aug 2020Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface...
Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ∼380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a large and complex network of interactions both within and across biological systems. We identified new PPIs for receptors with well-characterized ligands and binding partners for "orphan" receptors. New PPIs include proteins expressed on multiple cell types and involved in diverse processes including immune and nervous system development and function, differentiation/proliferation, metabolism, vascularization, and reproduction. These PPIs provide a resource for further biological investigation into their functional relevance and may offer new therapeutic drug targets.
Topics: DCC Receptor; Humans; Ligands; Phylogeny; Protein Interaction Maps; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Receptors, Cell Surface; Receptors, Interleukin-1; Signaling Lymphocytic Activation Molecule Family; Surface Plasmon Resonance
PubMed: 32822567
DOI: 10.1016/j.cell.2020.07.025 -
Cancer Research Oct 2020Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In...
Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In mesothelioma, we identified a highly specific tumor cell surface antigen that can be targeted for therapy development. Mesothelioma is caused by malignant transformation of the mesothelium, is incurable, and can be categorized into three histologic subtypes: epithelioid, biphasic, and sarcomatoid. To identity novel mesothelioma cell surface antigens with broad subtype coverage and high tissue specificity, we have previously selected phage antibody display libraries on live mesothelioma cells and tissues following counterselection on normal cells and identified a panel of human antibodies that bind all subtypes of mesothelioma, but not normal mesothelium. One of the antibodies, M25, showed high specificity against an antigen we identify here as ALPPL2. IHC on normal human tissues found that ALPPL2 is expressed only on placental trophoblasts, but not on any other normal tissues. This significant tissue specificity and broad tumor type coverage suggest that ALPPL2 could be an excellent cell surface target for therapeutic development against mesothelioma. To evaluate therapeutic potential of ALPPL2 targeting, an ALPPL2-targeted antibody-drug conjugate was developed and demonstrated potent and specific tumor killing and against both epithelioid and sarcomatoid mesothelioma. Thus, ALPPL2 belongs to a rare class of cell surface antigens classified as truly tumor specific and is well suited for therapy development against ALPPL2-expressing tumors. SIGNIFICANCE: These findings identify ALPP2 as a true tumor-specific cell surface antigen whose tissue specificity enables the development of novel therapies.
Topics: Alkaline Phosphatase; Animals; Antigens, Surface; Antineoplastic Agents, Immunological; CHO Cells; Cell Line, Tumor; Cricetulus; Epitopes; Female; GPI-Linked Proteins; Humans; Immunoconjugates; Immunoglobulin G; Male; Mesothelioma, Malignant; Mice, Inbred NOD; Molecular Targeted Therapy; Xenograft Model Antitumor Assays
PubMed: 32868383
DOI: 10.1158/0008-5472.CAN-20-1418 -
Cell Surface (Amsterdam, Netherlands) Dec 2023EXTENSINS (EXTs) are an abundant and yet enigmatic class of cell wall proteins that are found across multicellular plant lineages, from Bryophytes to Angiosperms. They... (Review)
Review
EXTENSINS (EXTs) are an abundant and yet enigmatic class of cell wall proteins that are found across multicellular plant lineages, from Bryophytes to Angiosperms. They have been shown to be integrated within the cell wall matrix, and are proposed to play key roles in the dynamic regulation of cell-wall properties. Consistent with this, EXTs are thought to be important for plant growth and development. However, like many other classes of cell wall proteins, EXTs are biochemically complex, highly diverse, and are encoded by multiple genes, making in-depth functional characterization a challenging undertaking. Here we will provide an overview of current knowledge of the biochemistry and properties of EXTs, and of the tools that have been deployed to study their biological functions in plants.
PubMed: 36659959
DOI: 10.1016/j.tcsw.2023.100094 -
The Journal of Experimental Medicine Apr 2020Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny...
Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in this model and define a unique subset of CD163+ Tim4+ resident omental macrophages responsible for metastatic spread of ovarian cancer cells. Transcriptomic analysis showed that resident CD163+ Tim4+ omental macrophages were phenotypically distinct and maintained their resident identity during tumor growth. Selective depletion of CD163+ Tim4+ macrophages in omentum using genetic and pharmacological tools prevented tumor progression and metastatic spread of disease. These studies describe a specific role for tissue-resident macrophages in the invasive progression of metastatic ovarian cancer. The molecular pathways of cross-talk between tissue-resident macrophages and disseminated cancer cells may represent new targets to prevent metastasis and disease recurrence.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Disease Models, Animal; Disease Progression; Female; Gene Expression Profiling; Macrophages; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Omentum; Ovarian Neoplasms; Peritoneal Neoplasms; Phenotype; Receptors, Cell Surface; Transcriptome
PubMed: 31951251
DOI: 10.1084/jem.20191869 -
Nature Aug 2022The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate...
The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes. Despite their therapeutic potential, our map of these surface interactions remains incomplete. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.
Topics: Cell Communication; Humans; Immune System; Leukocytes; Protein Binding; Protein Interaction Maps; Proteome; Receptors, Cell Surface
PubMed: 35922511
DOI: 10.1038/s41586-022-05028-x