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| Open AccessCis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
Notch signaling is critical for HSC emergence. Here, the authors identify a sub-set of hemogenic endothelial cells with high Notch activity that it is gradually shut down through cis inhibition of NOTCH1 by JAG1, and report that this process sustains HSC.
- Roshana Thambyrajah
- , Maria Maqueda
- & Anna Bigas
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Article
| Open AccessPhosphorylation of plasma membrane H+-ATPase Thr881 participates in light-induced stomatal opening
Comprehensive phosphoproteomic analysis using guard cell protoplasts revealed that Thr881 phosphorylation in addition of a penultimate residue, Thr948 of plasma membrane H+-ATPase are important for its function and light-induced stomatal opening.
- Yuki Hayashi
- , Kohei Fukatsu
- & Toshinori Kinoshita
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Article
| Open AccessLight-induced stomatal opening requires phosphorylation of the C-terminal autoinhibitory domain of plasma membrane H+-ATPase
Light-induced stomatal opening is crucial for photosynthesis. Here the authors show that blue light triggers phosphorylation of two Thr residues in the C-terminal autoinhibitory domain of plasma membrane H+-ATPase, thereby promoting stomatal opening.
- Saashia Fuji
- , Shota Yamauchi
- & Atsushi Takemiya
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Article
| Open AccessPIBF1 regulates trophoblast syncytialization and promotes cardiovascular development
The genetic link between placenta function and congenital heart defects has been established, though the cellular mechanisms underlying this connection is less clear. Here they show that PIBF1 regulates syncytiotrophoblast fusion and that loss of PIBF1 also negatively impacts heart development, providing a potential link between the development of these two organs.
- Jong Geol Lee
- , Jung-Min Yon
- & In-Jeoung Baek
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Comment
| Open AccessDIAPH1-MFN2 interaction decreases the endoplasmic reticulum-mitochondrial distance and promotes cardiac injury following myocardial ischemia
Contact between organelles such as the mitochondria (Mito) and endoplasmic reticulum (ER) is crucial to coordinate vital cellular homeostatic processes. Here we discuss recent work showing that Mito-ER proximity is regulated by heterotypic complexes between the F-actin polymerizing protein Diaphanous-1) and the mitochondrial dynamics protein Mitofusin 2, which confers increased susceptibility to ischemia/reperfusion injury.
- Lorrie A. Kirshenbaum
- , Rimpy Dhingra
- & Sergio Lavandero
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Article
| Open AccessRegulation of long-range BMP gradients and embryonic polarity by propagation of local calcium-firing activity
Identical twins from a single embryo are formed in multiple species, albeit rarely. It is not clear how such twinning is suppressed during early development. Here they show that calcium signalling activity is propagated through the extraembryonic tissue to prevent ectopic primitive streak formation during gastrulation.
- Hyung Chul Lee
- , Nidia M. M. Oliveira
- & Claudio D. Stern
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Article
| Open AccessDistinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Here the authors screen a saturation mutagenesis library of the disordered N-terminal tail of the actin severing protein cofilin. Their results reveal how a key phosphorylation site can balance competing sequence constraints on function and regulation.
- Joel A. Sexton
- , Tony Potchernikov
- & Benjamin E. Turk
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Article
| Open AccessMolecular basis of VEGFR1 autoinhibition at the plasma membrane
Spontaneous activation of VEGFRs is a hallmark of diabetes and several cancers. Here, the authors show how in VEGFR1 a juxtamembrane segment connecting the catalytic and ligand-binding domains of the receptor can prevent its spontaneous activation.
- Manas Pratim Chakraborty
- , Diptatanu Das
- & Rahul Das
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Article
| Open AccessAggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer
The role of aggresomes in tumorigenesis and cancer progression remains to be explored. Here, the authors perform multi-omics and reveal that aggresome formation supports ovarian cancer stem cell properties via OTUD1 and ASK1/JNK signalling activation.
- Yurou Chen
- , Yulong Qiang
- & Feng Li
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Article
| Open AccessHKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression
Aberrant expression of the human hexokinase HKDC1 has been observed in patients with cancer. Here the authors report that HKDC1 expression is associated with hepatocellular carcinoma progression and PD-L1 mediated immune evasion.
- Yi Zhang
- , Mingjie Wang
- & Ping Gao
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Article
| Open AccessKisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src
The authors of this manuscript identify that Gpr54 activation by its natural ligand Kisspeptin-10 can abrogate bone resorption. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase, which causes Dusp18 to dephosphorylate Src at Tyr 416.
- Zhenxi Li
- , Xinghai Yang
- & Jianru Xiao
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Article
| Open AccessTFIP11 promotes replication fork reversal to preserve genome stability
The RAD51 recombinase plays a pivotal role in replication fork reversal during replication stress. Here, the authors show that the GCFC domain-containing protein TFIP11 interacts with BLM helicase and is important for fork reversal during replication stress to preserve genome stability.
- Junliang Chen
- , Mingjie Wu
- & Ting Liu
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Article
| Open AccessPhosphorylation of Arabidopsis UVR8 photoreceptor modulates protein interactions and responses to UV-B radiation
This paper reports that the Arabidopsis UV-B photoreceptor UVR8 is phosphorylated in vivo and that phosphorylation of Serine 402 modifies UVR8 activity and promotes flavonoid biosynthesis, a key response to UV-B exposure.
- Wei Liu
- , Giovanni Giuriani
- & Gareth I. Jenkins
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Article
| Open AccessAndrogen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation
Mechanisms underlying sex associated differences in the role of androgen receptor (AR) in melanoma are unclear. Here the authors show that androgen-activated AR transcriptionally upregulates fucosyltransferase 4, which fucosylates L1CAM and promotes melanoma invasiveness by disrupting adherens junctions.
- Qian Liu
- , Emma Adhikari
- & Eric K. Lau
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Article
| Open AccessDiffusible fraction of niche BMP ligand safeguards stem-cell differentiation
The activity of Drosophila male germline stem cells is tightly regulated by a cluster of somatic niche cells. Here they find that Dpp induces opposed cellular responses in stem cells versus in differentiating descendants, thereby ensuring spatial control of the niche with a single factor.
- Sharif M. Ridwan
- , Autumn Twillie
- & Mayu Inaba
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Article
| Open AccessPhosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome
The epidermal growth factor receptor (EGFR) plays important roles in cell growth and motility. Here, authors reveal an unexpected function for a metabolic enzyme PGK1 and advance the mechanistic understanding of lysosomal transport of EGFR.
- Shao-Ling Chu
- , Jia-Rong Huang
- & Jia-Wei Hsu
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Article
| Open AccessR-Spondin 2 governs Xenopus left-right body axis formation by establishing an FGF signaling gradient
Left-right (LR) body asymmetry is established by leftward flow in the LR organizer. Here, the authors show in Xenopus that R-Spondin 2 acts as an FGF receptor antagonist that produces a right-to-left FGF signaling gradient in response to flow to break LR symmetry.
- Hyeyoon Lee
- , Celine Marie Camuto
- & Christof Niehrs
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Article
| Open AccessRescue of mitochondrial import failure by intercellular organellar transfer
Mitochondrial biogenesis and maintenance relies on protein import from the cytosol. Here, authors show that import failure impacts organelle structure and dynamics. They also identify a rescue mechanism involving intercellular mitochondrial transfer.
- Hope I. Needs
- , Emily Glover
- & Ian Collinson
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Article
| Open AccessCaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses
Calmodulin-dependent kinase 4 (CaMK4) has been implicated in humoral immunity. Here, the authors demonstrate that CaMK4 expression controls the differentiation of T follicular helper cells, leading to the expansion of pathogenic B cells in systemic lupus erythematosus.
- Marc Scherlinger
- , Hao Li
- & George C. Tsokos
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Article
| Open AccessActivation 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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Article
| Open AccessSoluble and multivalent Jag1 DNA origami nanopatterns activate Notch without pulling force
The Notch receptor is known to be activated by a pulling force, but whether it is strictly required remains to be clarified. Here, the authors demonstrate activation of Notch through soluble multivalent DNA origami constructs, showing effects in neuroepithelial-like stem cells.
- Ioanna Smyrlaki
- , Ferenc Fördős
- & Björn Högberg
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Article
| Open AccessDiabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
The mechanisms underlying diabetic neuropathy remain elusive. Here, the authors identify that UCHL1 deubiquitinase positively regulates insulin signaling and its loss leads to axonal degeneration of sensory neurons.
- Daewon Lee
- , Eunju Yoon
- & Jongkyeong Chung
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Article
| Open AccessEpstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.
- Fabian Giehler
- , Michael S. Ostertag
- & Arnd Kieser
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Article
| Open AccessMcam inhibits macrophage-mediated development of mammary gland through non-canonical Wnt signaling
Mammary epithelial cells act to continuously renew the mammary tissue and must balance differentiation and self-renewal. Here they show that Mcam, a non-canonical Wnt pathway member, regulates communication between macrophages and mammary epithelial cells, thereby maintaining self-renewal and subsequently promoting mammary ductal morphogenesis.
- Xing Yang
- , Haibo Xu
- & Baowei Jiao
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Article
| Open AccessHijacking of internal calcium dynamics by intracellularly residing viral rhodopsins
Rhodopsins are ubiquitous light-driven membrane proteins that have diverse functions in nature, and value as optogenetics tools. Here the authors characterise type 1 viral channelrhodopsins, showing that they regulate intracellular calcium and can be used for the photocontrol of muscle contraction in vivo.
- Ana-Sofia Eria-Oliveira
- , Mathilde Folacci
- & Michel Vivaudou
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Article
| Open AccessInnate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis
The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.
- Yinan Yang
- , Huijing Zhou
- & Bo Liu
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Article
| Open AccessRedox-enabled electronic interrogation and feedback control of hierarchical and networked biological systems
With redox-linked synthetic biology and electrobiofabrication, electronic information can be transmitted in a bidirectional manner between biology and electronics. Here the authors design an electrogenetic platform that allows real time electronic control of biological functions from proteins and gene circuits to cell consortia.
- Sally Wang
- , Chen-Yu Chen
- & William E. Bentley
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Article
| Open AccessVWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes
mTORC1 adapts cellular metabolism in response to nutrient signals. Here, the authors identify VWCE as a negative regulator of amino acid-dependent mTORC1 signaling and a potential as a therapeutic target in prostate cancer treatments.
- Tianyu Zhao
- , Yuanyuan Guan
- & Ying Liu
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Article
| Open AccessDissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans
To overcome challenges posted by vast number of GPCR genes and redundancy, the authors disrupted nearly all GPCR-encoding genes in C. elegans, enabling effective examination of GPCR signaling and offering a valuable resource for the research community.
- Longjun Pu
- , Jing Wang
- & Changchun Chen
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Article
| Open AccessThe function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways
Berkane et al. investigated the activation process of selective autophagy of the ER. They show that that phosphorylation of FAM134 proteins by CK2 is a prerequisite for the formation of large micro-clusters of high-density at the ER membrane.
- Rayene Berkane
- , Hung Ho-Xuan
- & Alexandra Stolz
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Article
| Open AccessRho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles
Cell movements are achieved by the spatio-temporal coordination of local membrane protrusions and retractions. Here, the authors identify a mechanism by which these protrusion and retraction events are coupled and how this affects the directionality of cell movements.
- Suchet Nanda
- , Abram Calderon
- & Leif Dehmelt
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Article
| Open AccessCytoglobin regulates NO-dependent cilia motility and organ laterality during development
Developmental defects in left-right cardiac determination in humans are associated with ciliary dysfunction and low airway epithelial nitric oxide production. Here, the authors show that cytoglobin is essential for nitric oxide signaling, cilia function, and left-right patterning during zebrafish development.
- Elizabeth R. Rochon
- , Jianmin Xue
- & Paola Corti
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Article
| Open AccessStructures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity
Cryo-EM structures reveal the molecular mechanism of ligands and G protein selectivity for prostaglandin F2α receptor, providing guidance for development of better postpartum hemorrhage drugs.
- Xiuqing Lv
- , Kaixuan Gao
- & Xiangyu Liu
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Matters Arising
| Open AccessReply to: How carvedilol does not activate β2-adrenoceptors
- Evi Kostenis
- , Jesus Gomeza
- & Stefan Schulz
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Article
| Open AccessCurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves
Dose-response curves are ubiquitous in pharmacology and biology, yet potency and effect size are often estimated even when there is no response. Here, authors present a statistical framework to assess curve significance and demonstrate how this aids drug mode of action analysis in large public datasets.
- Florian P. Bayer
- , Manuel Gander
- & Matthew The
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Article
| Open AccessA dynamic partitioning mechanism polarizes membrane protein distribution
Different membrane proteins dynamically polarize to organize signal transduction, but the underlying mechanism is unclear. Here, the authors show that a differential diffusion mediated partitioning process is sufficient to drive such spatiotemporal patterning of membrane-associated signaling proteins.
- Tatsat Banerjee
- , Satomi Matsuoka
- & Pablo A. Iglesias
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Article
| Open AccessNon-canonical pathway for Rb inactivation and external signaling coordinate cell-cycle entry without CDK4/6 activity
Cyclin-dependent kinases (CDK4/6) play a crucial role in initiating cell growth. Here, Zhang et al. unveil a mechanism that bypasses CDK4/6, shedding light on an alternative pathway of cell-cycle initiation and quiescence maintenance.
- Mimi Zhang
- , Sungsoo Kim
- & Hee Won Yang
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Article
| Open AccessEndosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36
Endosomal EGFR signaling and lysosomal degradation play important roles in controlling numerous biological processes. Here, the authors show that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.
- Shin-Jin Lin
- , Ming-Chieh Lin
- & Fang-Jen S. Lee
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Article
| Open AccessNod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
The signals that enable endothelial cells to switch to hemogenic to generate hematopoietic stem cells are poorly understood. Here, the authors identify an intracellular sensor of pathogens as an inductive developmental cue that primes this switch.
- Xiaoyi Cheng
- , Radwa Barakat
- & Raquel Espin-Palazon
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Article
| Open AccessStructures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant
Interleukin (IL-)11 is a signaling protein that plays key roles in several human diseases. Here the authors describe structures of IL-11 in complex with its receptors and determine the molecular mechanisms through which a variant of IL-11 inhibits signalling, opening avenues for therapeutic development.
- Riley D. Metcalfe
- , Eric Hanssen
- & Michael D. W. Griffin
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Article
| Open AccessTranscriptional responses of cancer cells to heat shock-inducing stimuli involve amplification of robust HSF1 binding
The authors compare the heat shock response between different cell lines and stimuli and reveal the genome-wide binding of its master transcription factor HSF1 as a platform for context-specific transcription activation.
- Sayantani Ghosh Dastidar
- , Bony De Kumar
- & Sergei Nechaev
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Article
| Open AccessHSP47 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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Article
| Open AccessEncystation stimuli sensing is mediated by adenylate cyclase AC2-dependent cAMP signaling in Giardia
Giardia lamblia is an established model for studying encystation. Shih et al show bile and alkaline pH induce changes in membrane ordering, upregulate cAMP, and initiate encystation gene expression.
- Han-Wei Shih
- , Germain C. M. Alas
- & Alexander R. Paredez
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Article
| Open AccessDetermining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB
Dorsal organizer initiates the dorsal-ventral axis formation in vertebrates. Here, the authors demonstrate that Tlr4/NFκB-mediated negative feedback regulation of Wnt/β-catenin signaling determines the precise size of the zebrafish dorsal organizer.
- Juqi Zou
- , Satoshi Anai
- & Tohru Ishitani
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Article
| Open AccessCell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function
During the activation and migration of T cells volume changes occur in response to osmolality cues which is not fully understood. Here the authors characterize the function of volume regulated ion channels in T cells and show that these channels regulate TCR sensitivity, thymic selection and TCR repertoire.
- Yuman Wang
- , Zaiqiao Sun
- & Ning Wu
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessHepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice
NASH, nonalcoholic steatohepatitis, a severe fatty liver disease with no cure, can manifest through loss-of-function of the E3 ligase FBXW7. Here, the authors show an underpinning of dysregulated ERRα and PPARα nuclear receptor activity, thus highlighting potential new avenues for antiNASH therapy.
- Hui Xia
- , Catherine R. Dufour
- & Vincent Giguère
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Article
| Open AccessCyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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Article
| Open AccessRemodeling the cellular stress response for enhanced genetic code expansion in mammalian cells
Genetic code expansion (GCE) is a protein engineering tool that enables programmed and site-specific installation of noncanonical amino acids into proteins. Here, authors show that cellular stress remodelling boosts GCE in mammalian cells including GCE realized by orthogonally translating organelles.
- Mikhail E. Sushkin
- , Christine Koehler
- & Edward A. Lemke