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Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis
Whether Kupffer cells play a role in regulating the pathogenesis of fatty liver disease remains to be completely explored. Here, the authors show GPR3 activation stimulates glycolysis in Kupffer cells through GPR3-β-arrestin2-GAPDHPKM2 pathway and inhibits high-fat diet induced obesity and liver pathogenesis.
- Ting Dong
- , Guangan Hu
- & Jianzhu Chen
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| Open Access
HSP47 levels determine the degree of body adiposity
A complex interplay of various backgrounds and conditions determines the body fat levels of individuals. Here, the authors identify HSP47 as a pivotal determinant of body adiposity which is abundantly expressed in fat tissue and influenced by factors such as diet, exercise, hormones, and genetics.
- Jihoon Shin
- , Shinichiro Toyoda
- & Iichiro Shimomura
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Monolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification
Generation of primordial germ cell-like cells (PGCLCs) from human pluripotent cells (hPSCs) offers insight into the mechanisms underlying human reproduction, but often requires complex methods. Here they describe a simplified monolayer protocol to differentiate and purify PGCLCs for further analysis.
- Sivakamasundari Vijayakumar
- , Roberta Sala
- & Vittorio Sebastiano
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Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity
The microvasculature is critical for delivery of oxygen and metabolites throughout tissues. Here they use human blood vessel organoids to show that CTGF is a critical paracrine regulator of microvascular integrity that can restore pericyte coverage and vessel structure.
- Sara G. Romeo
- , Ilaria Secco
- & Anna Zampetaki
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Deciphering intercellular signaling complexes by interaction-guided chemical proteomics
Systematic profiling of the indirect cell–cell interactions remains challenging. Here, the authors report a chemical proteomics method to identify ligand-receptor complexes formed between cell surface receptors and secreted proteins from neighboring cells.
- Jiangnan Zheng
- , Zhendong Zheng
- & Ruijun Tian
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Subcellular second messenger networks drive distinct repellent-induced axon behaviors
Signals from extracellular cues orienting growing axons are thought to be integrated by second messenger molecules. Here, Baudet et al. instead demonstrate that distinct axon guidance cues induce cAMP, cGMP and Ca2+ signals restricted to separate cellular nanodomains.
- Sarah Baudet
- , Yvrick Zagar
- & Xavier Nicol
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Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche
Most intestinal organoid models do not accurately model the interactions between epithelial and stromal cells. Here they establish a colon assembloid system with epithelial and stromal cells and demonstrate that BMP signals from differentiating epithelial cells promote mesenchymal niche organization.
- Manqiang Lin
- , Kimberly Hartl
- & Michael Sigal
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| Open Access
p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response
The p140Cap adaptor protein is a tumour suppressor associated with improved prognosis in breast cancer. Here, the authors identify a role for p140Cap in preventing the immunosuppressive and pro-tumour function of polymorphonuclear myeloid-derived suppressor cells via downmodulation of the β-Catenin/Tumor Initiating Cells/G-CSF axi
- Vincenzo Salemme
- , Mauro Vedelago
- & Paola Defilippi
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Ligand-induced activation and G protein coupling of prostaglandin F2α receptor
Prostaglandin F2α receptor (FP) is the primary therapeutic target for glaucoma and several other diseases. Here, the authors reveal structural mechanisms of ligand recognition, receptor activation, and G protein coupling by FP.
- Canrong Wu
- , Youwei Xu
- & H. Eric Xu
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Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling
EGFR is a receptor that is upregulated in many cancers, but the mechanisms that control EGFR function are incompletely understood. Here the authors used single particle tracking to identify a role for tetraspanin CD81 in EGFR ligand binding, mobility, and signaling.
- Michael G. Sugiyama
- , Aidan I. Brown
- & Costin N. Antonescu
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A small secreted protein NICOL regulates lumicrine-mediated sperm maturation and male fertility
Mammalian sperm need to be matured in the epididymis to achieve potential for fertility. Here the authors identify NICOL as a secreted protein that acts on the epididymis to trigger its functional differentiation and induce sperm maturation.
- Daiji Kiyozumi
- , Kentaro Shimada
- & Masahito Ikawa
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| Open Access
A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates
Here, the authors show that cell internalization of Engrailed2 not only relies on its homeodomain, but also involves a cationic region which interacts selectively with cell surface heparan sulfates.
- Sébastien Cardon
- , Yadira P. Hervis
- & Sandrine Sagan
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Antigen footprint governs activation of the B cell receptor
The antigen-B-cell-receptor interaction is the driving force of terminal B cell development that spans from B cell activation to antibody secreting plasma cells. Here authors determine, using DNA-PAINT super-resolution microscopy, how antigen affinity and valency define antigen binding to BCR in an in vitro system allowing precision control of these parameters.
- Alexey Ferapontov
- , Marjan Omer
- & Søren Egedal Degn
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SVEP1 is an endogenous ligand for the orphan receptor PEAR1
SVEP1 is linked to numerous human diseases, though its disease-promoting mechanism has remained unclear. Here, the authors identify SVEP1 as a ligand for the orphan receptor PEAR1 and provide insight into the role of this interaction in cardiovascular disease.
- Jared S. Elenbaas
- , Upasana Pudupakkam
- & Nathan O. Stitziel
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A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis
The signaling mechanisms regulating adipose thermogenesis have not been fully elucidated. Here, the authors show that a brown fat-enriched adipokine ADISSP promotes adipose thermogenesis and improves metabolic health independently of b-adrenergic receptor.
- Qingbo Chen
- , Lei Huang
- & Yong-Xu Wang
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How Carvedilol activates β2-adrenoceptors
How carvedilol, a β1-blocker, activates β2-adrenoceptors, is unclear. Here, the authors resolve this enigma and show that carvedilol drives all of its detectable cellular β2-adrenoceptor signals by slow and low efficacy G protein activation.
- Tobias Benkel
- , Mirjam Zimmermann
- & Evi Kostenis
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An extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation
Specificity in signaling activated by receptor tyrosine kinases is typically attributed to characteristics of their intracellular domains. Here, the authors demonstrate that an extracellular receptor sequence motif controls intracellular signaling as a result of extracellular glycan interactions.
- Katri Vaparanta
- , Anne Jokilammi
- & Klaus Elenius
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Epithelial coxsackievirus adenovirus receptor promotes house dust mite-induced lung inflammation
The epithelial protein Coxsackievirus Adenovirus Receptor (CAR) is a virus receptor but may have other functions. Here the authors show that deletion of CAR in mice leads to reduced house dust mite-induced lung inflammation, reduced neutrophil accumulation and alterations in airway remodelling.
- Elena Ortiz-Zapater
- , Dustin C. Bagley
- & Maddy Parsons
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Engineered cell differentiation and sexual reproduction in probiotic and mating yeasts
G protein-coupled receptors (GPCRs) enable cells to sense environmental cues and are indispensable for coordinating vital processes including quorum sensing, proliferation, and sexual reproduction. Here the authors, using heterologous GPCR expression and endogenous ligand production, enable synthetic mating in haploid yeast, and GPCR-mediated biosensing in diploid probiotic yeast.
- Emil D. Jensen
- , Marcus Deichmann
- & Michael K. Jensen
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HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors
Lack of CD8+ T-cell infiltration into solid tumors is associated with poor responsiveness to immune checkpoint therapy (ICT). Here, the authors show that blocking the phosphorylation of HRS to reduce the induction of immunosuppressive exosomes promotes CD8+ T-cell infiltration into tumors and enhances the efficacy of ICT in mouse melanoma models.
- Lei Guan
- , Bin Wu
- & Wei Guo
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The encephalomyocarditis virus Leader promotes the release of virions inside extracellular vesicles via the induction of secretory autophagy
Picornaviruses can escape infected cells via packaging in extracellular vesicles (EVs). Here, van der Grein et al. show that the non-structural Leader protein of encephalomyocarditis virus (EMCV) promotes the release of EV-enclosed virus particles and provide evidence for a role of secretory autophagy in this process.
- Susanne G. van der Grein
- , Kyra A. Y. Defourny
- & Esther N. M. Nolte-‘t Hoen
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T-cell trans-synaptic vesicles are distinct and carry greater effector content than constitutive extracellular vesicles
T cells communicate with antigen-presenting cells (APC) via the signaling crosstalk at the immunological synapse (IS). Here the authors use bead-supported lipid bilayers as synthetic APCs to find that trans-synaptic vesicles produced by T cells in the IS carry specialized cargos distinct from constitutive extracellular vesicles to serve as intercellular messengers.
- Pablo F. Céspedes
- , Ashwin Jainarayanan
- & Michael L. Dustin
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GPI-anchored FGF directs cytoneme-mediated bidirectional contacts to regulate its tissue-specific dispersion
Cytonemes are signaling filopodia that mediate target-specific long-distance communications of signals like FGFs. Du et al. show that a Drosophila FGF is anchored to the FGF-producing cell surface, inhibiting free FGF secretion and activating contact-dependent bidirectional FGF-FGFR interactions, controlling target-specific cytoneme contacts and contact-dependent FGF release.
- Lijuan Du
- , Alex Sohr
- & Sougata Roy
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CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation
Intestinal stem cells contribute to homeostasis through a balance between self-renewal and differentiation. Here the authors show that CCN1 is an intestinal stem cell niche factor that activates integrin αvβ3/αvβ5 signaling to regulate proliferation and differentiation through distinct downstream pathways.
- Jong Hoon Won
- , Jacob S. Choi
- & Joon-Il Jun
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Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Interferon alpha (IFNalpha) therapy is showing promising results to treat myeloproliferative neoplasms (MPNs). Here, the authors show that IFNalpha response requires ULK1 phosphorylation to induce p38-MAPK signalling but it is counteracted by ROCK1-2 activation suggesting combination therapy of IFNalpha-ROCK1-2 inhibition may improve MPNs treatment.
- Diana Saleiro
- , Jeremy Q. Wen
- & Leonidas C. Platanias
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Breast tissue regeneration is driven by cell-matrix interactions coordinating multi-lineage stem cell differentiation through DDR1
Mammary morphogenesis is a complex process. Here the authors describe how stem cells build a three-dimensional self-organizing multi-lineage tissue by showing that positional signals from the extracellular matrix through the collagen receptor DDR1 lead stem cells to differentiate into multi-lineage committed multi-layered progeny.
- Gat Rauner
- , Dexter X. Jin
- & Charlotte Kuperwasser
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Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling
Hedgehog-Interacting Protein (HHIP) is the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling. Here, the authors report structures of the HHIP N- and C-terminal domains, both in complexes with glycosaminoglycans, providing insights into the molecular basis for SHH sequestration and inhibition.
- Samuel C. Griffiths
- , Rebekka A. Schwab
- & Christian Siebold
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Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors
Yolk sac erythro-myeloid progenitors (EMPs) are critical for embryo viability and a major source of adult tissue-resident macrophages. Here, the authors show an essential stage-specific role for Ezh2 in modulating Wnt signaling during EMP generation.
- Wen Hao Neo
- , Yiran Meng
- & Georges Lacaud
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Light-mediated discovery of surfaceome nanoscale organization and intercellular receptor interaction networks
The spatial organization of cell surface receptors is critical for cell signaling and drug action. Here, the authors develop an optoproteomic method for mapping surface protein interactions, revealing cellular responses to antibodies, drugs and viral particles as well as immunosynapse signaling events.
- Maik Müller
- , Fabienne Gräbnitz
- & Bernd Wollscheid
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A somatic proteoglycan controls Notch-directed germ cell fate
Notch receptor GLP-1 is required for maintaining germ cells in the C. elegans germline. Here the authors show that syndecan-1, a somatic transmembrane proteoglycan regulates expression of glp-1 and germ cell mitosis in C. elegans, by promoting calcium-dependent binding of APTF-2 to the glp-1 promoter.
- Sandeep Gopal
- , Aqilah Amran
- & Roger Pocock
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| Open Access
GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain
GAPDH is generally considered a housekeeping gene and functions in glycolysis. Here, the authors show that GAPDH has a role in promoting vesicle clustering in endosomes and can load siRNA onto the surface of extracellular vesicles, which can be exploited therapeutically.
- Ghulam Hassan Dar
- , Cláudia C. Mendes
- & Matthew J. A. Wood
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Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors
Concomitant traumatic brain injury accelerates bone healing, but the mechanism is unclear. Here, the authors show that injured neurons, mainly those in the hippocampus, release osteogenic miRNA-enriched small extracellular vesicles, which targete osteoprogenitors to stimulate bone formation.
- Wei Xia
- , Jing Xie
- & Xiaochun Bai
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The GPR171 pathway suppresses T cell activation and limits antitumor immunity
Proliferative and effector functions of T cells are determined by T cell receptor signalling and modulated by activator and inhibitory co-receptors. Authors report here that the G-protein-coupled receptor GPR171 functions as a co-inhibitor of T cell signalling and might serve as a target for cancer immunotherapy.
- Yuki Fujiwara
- , Robert J. Torphy
- & Yuwen Zhu
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Extracellular mRNA transported to the nucleus exerts translation-independent function
Nonvesicular extracellular RNA (nex-RNA) that are not packed in extracellular vesicles is detected outside the cell, but it is poorly understood. Here the authors report that nex-RNA is captured by a zinc finger protein and transported to the nucleus to enhance antimetastatic characters of the cell.
- Takeshi Tomita
- , Masayoshi Kato
- & Sachie Hiratsuka
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Proteomics of protein trafficking by in vivo tissue-specific labeling
The network of proteins secreted for interorgan communication is poorly understood. Here, the authors develop a method, based on protein labeling, to study cell-specific secretomes and interorgan protein trafficking, and demonstrate their approach in Drosophila and mouse models.
- Ilia A. Droujinine
- , Amanda S. Meyer
- & Norbert Perrimon
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Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling
Cytonemes are cellular projections known to transfer Wnt ligands between cells, but their regulation remains unclear. Here, the authors show that activation of the planar cell polarity protein Vangl2 generates long and branched cytonemes increasing paracrine Wnt/β-catenin signaling.
- Lucy Brunt
- , Gediminas Greicius
- & Steffen Scholpp
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Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF
Small molecules stabilising a distorted TNF trimer can inhibit TNF signaling, but the underlying mechanism is unclear. Here, the authors characterize the inhibitor-bound TNF-receptor complex structurally and biochemically, showing that the inhibitors alter TNF-receptor binding stoichiometry and cluster formation.
- David McMillan
- , Carlos Martinez-Fleites
- & James O’Connell
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| Open Access
Sensing of autoinducer-2 by functionally distinct receptors in prokaryotes
The small molecule AI-2 acts as a quorum sensing signal, mediating communication within and between many bacterial species. Here, the authors identify a new type of AI-2 receptor, consisting of a dCACHE domain that is present in many bacterial and archaeal proteins.
- Lei Zhang
- , Shuyu Li
- & Xihui Shen
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Article
| Open Access
Cell-surface receptors enable perception of extracellular cytokinins
The main site of cytokinin perception in plant cells is thought to be the endoplasmic reticulum where most cytokinin receptors localise. Here via the use of bioactive probes that cannot enter plant cells and super-resolution microscopy, Antoniadi et al. show that cytokinin can also be perceived at the plasma membrane.
- Ioanna Antoniadi
- , Ondřej Novák
- & Colin Turnbull
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| Open Access
ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells
The integrin ITGB3 has been described to play an essential role in breast cancer metastasis, but the precise mechanisms remain undefined. Here the authors describe thus far unknown roles of ITGB3 in the uptake of extracellular vesicles, required for colony growth of breast cancer cells.
- Pedro Fuentes
- , Marta Sesé
- & Santiago Ramón y Cajal
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| Open Access
Basement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue
The molecular mechanisms regulating macrophage recruitment to tumors are unclear. Here, the authors use a Drosophila overgrowth model to show how damaged basement membranes recruit macrophages to undead tissue, via an interdependent effect of reactive oxygen species and matrix metalloproteinase 2.
- Neha Diwanji
- & Andreas Bergmann
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| Open Access
The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides
Opioids modulate pain, anxiety and stress by activating four subtypes of opioid receptors. The authors show that atypical chemokine receptor 3 (ACKR3) is a scavenger for various endogenous opioid peptides regulating their availability without activating downstream signaling.
- Max Meyrath
- , Martyna Szpakowska
- & Andy Chevigné
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| Open Access
RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro
Genetic variants at the RSPO3 locus are associated with waist-to-hip ratio (adjusted for BMI). Here, Loh et al. describe two independent RSPO3 signals that associate with body fat distribution, perform fine-mapping and explore the function of RSPO3 in human adipocyte biology and body fat distribution in zebrafish
- Nellie Y. Loh
- , James E. N. Minchin
- & Constantinos Christodoulides
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| Open Access
Lgr5+ telocytes are a signaling source at the intestinal villus tip
Epithelial gene expression has been shown to be zonated along the crypt-villus axis, but mechanisms shaping this spatial variability were unknown. Here, Bahar Halpern et al. uncover zonation of mesenchymal cells, including Lgr5+ telocytes, which regulate epithelial gene expression at the villus tip.
- Keren Bahar Halpern
- , Hassan Massalha
- & Shalev Itzkovitz
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| Open Access
A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma
The MET receptor is frequently activated in cancer. Here, the authors show that in head and neck and lung squamous carcinoma, a polymorphic MET variant enhances binding to HER2, resulting in activation of HER2 signalling and progression of the cancers.
- Li Ren Kong
- , Nur Afiqah Binte Mohamed Salleh
- & Boon Cher Goh
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| Open Access
Ratiometric population sensing by a pump-probe signaling system in Bacillus subtilis
Gram-positive bacteria can release signaling peptides that are ‘probed’ by intracellular receptors after being pumped into the cytoplasm. Here, Babel et al. show that these pump-probe networks can infer the fraction of signal-producing cells in a mixed population, and do not necessarily mediate typical quorum-sensing control.
- Heiko Babel
- , Pablo Naranjo-Meneses
- & Ilka B. Bischofs
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| Open Access
Liver governs adipose remodelling via extracellular vesicles in response to lipid overload
Extracellular vesicles (EVs) containing miRNAs or proteins can coordinate metabolic responses between tissues. Here the authors demonstrate that during lipid overload, the liver secretes miRNA-containing EVs through a Ggpps-Rab27 dependent mechanism, which controls adipose tissue lipid storage capacity.
- Yue Zhao
- , Meng-Fei Zhao
- & Chao-Jun Li
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| Open Access
Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche
Acetylcholine regulates intestinal epithelial secretion via muscarinic Gq-coupled receptors but its role in cell differentiation is unclear. Here, the authors show that Prox1-positive endocrine cells are sensors for the cholinergic intestinal niche and can trigger increased differentiation of enteroendocrine DCLK1-positive tuft cells.
- Moritz Middelhoff
- , Henrik Nienhüser
- & Timothy C. Wang
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| Open Access
A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing
Decreased autophagy is a hallmark of ageing, but its inter-tissue regulation is poorly understood. Here, Zhou et al. identify mir-83 in C. elegans, which is transported across tissues and suppresses autophagy, contributing to age-related decline.
- Yifei Zhou
- , Xueqing Wang
- & Yidong Shen
Host response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1