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| Open AccessChemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis
Deregulation of BCL-2 proteins ensures resistance to apoptosis. Here, the authors describe cytosolic BAX dimers, which in cancer cells inhibit BAX activation and they develop a strategy to modulate BAX dimers to potentiate BAX-mediated apoptosis.
- Nadege Gitego
- , Bogos Agianian
- & Evripidis Gavathiotis
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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 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 AccessA single C-terminal residue controls SARS-CoV-2 spike trafficking and incorporation into VLPs
Dey et al. use structure-function methods to show that partial mimicry of the coatomer-binding motif in the SARS-CoV-2 spike is crucial for its release post coatomer-dependent delivery, thus ensuring optimal spike fusogenicity and VLP incorporation.
- Debajit Dey
- , Enya Qing
- & S. Saif Hasan
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Article
| Open AccessMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57Kip2.
- Silvia Pomella
- , Matteo Cassandri
- & Rossella Rota
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Article
| Open AccessUbiquitination-mediated Golgi-to-endosome sorting determines the toxin-antidote duality of fission yeast wtf meiotic drivers
Meiotic drivers of the wtf family kill progeny lacking the driver by producing a toxin and an antidote. Here, authors reveal that ubiquitination-mediated sorting of the antidote prevents it from becoming toxic and enables it to neutralize the toxin.
- Jin-Xin Zheng
- , Tong-Yang Du
- & Li-Lin Du
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Article
| Open AccessMolecular basis and cellular functions of vinculin-actin directional catch bonding
This study provides insights into the directional catch bonding of the linker protein vinculin by elucidating the molecular basis of mechanical reinforcement as well as unveiling its key role in subcellular organization and cellular processes.
- Venkat R. Chirasani
- , Mohammad Ashhar I. Khan
- & Sharon L. Campbell
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Article
| Open AccessOn the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging
Tryptophan metabolism through the kynurenine pathway changes with age and represents a potential intervention target for age associated disease. Here, the authors show that elevating physiological levels of the kynurenine pathway metabolite 3- hydroxyanthranilic acid can promote healthy aging.
- Hope Dang
- , Raul Castro-Portuguez
- & George L. Sutphin
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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 AccessRemodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases
Here, the authors show how the vDUB from the large tegument protein from the human herpes virus can reprogram translation in host cells by modulating the activity of the ribosome quality machinery and activating the integrated stress response.
- Jiangnan Liu
- , Noemi Nagy
- & Maria G. Masucci
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Article
| Open AccessZNF524 directly interacts with telomeric DNA and supports telomere integrity
ZNF524 is a newly described protein that binds to telomeres, the ends of linear chromosomes. ZNF524 promotes the presence of two members of the shelterin complex, TRF2/RAP1, at telomeres, and prevents genomic instability.
- Hanna Braun
- , Ziyan Xu
- & Dennis Kappei
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Article
| Open AccessCENP-A and CENP-B collaborate to create an open centromeric chromatin state
Centromeres are defined by the histone variant CENP-A. Using single-molecule fluorescence and cryoEM, this study shows that CENP-A and the centromeric protein CENP-B collaborate to create dynamic and open chromatin, aiding centromeric factor binding.
- Harsh Nagpal
- , Ahmad Ali-Ahmad
- & Beat Fierz
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Article
| Open AccessSingle-photon microscopy to study biomolecular condensates
The wide variety of cellular processes involving biomolecular condensation makes their quantification a challenging task. Here, the authors present an integrated platform based on single-photon microscopy to study complex biomolecular processes.
- Eleonora Perego
- , Sabrina Zappone
- & Giuseppe Vicidomini
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Article
| Open AccessGRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis
Cytoskeletal remodeling is known to facilitate mitophagy, but the mechanism is not fully understood. Here, the authors show that damaged mitochondria recruit a RhoA GTPase activating protein that promotes their capture and encasement by autophagosomes.
- Qiang Zhu
- , Matthew E. Combs
- & Joan M. Taylor
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Article
| Open AccessInterleukin 31 receptor α promotes smooth muscle cell contraction and airway hyperresponsiveness in asthma
Although IL-31 has been implicated in asthma, the exact contribution of the IL-31 receptor (IL-31RA) signalling to airway hyperresponsiveness remains unexplored. Here, the authors demonstrate that IL31RA promotes muscarinic acetylcholine receptor 3 expression and calcium signalling, as well as smooth muscle cell contraction.
- Santhoshi V. Akkenepally
- , Dan J. K. Yombo
- & Satish K. Madala
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Article
| Open AccessThe long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis
Although patients with rheumatoid arthritis (RA) usually exhibit symmetrical joint involvement, some can develop alternative patterns of arthritis, often translating into differences in responsiveness to treatment. In this study, the authors propose that the long-noncoding RNA, HOTAIR, might contribute to these differences.
- Muriel Elhai
- , Raphael Micheroli
- & Caroline Ospelt
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Article
| Open AccessThe NERP-4–SNAT2 axis regulates pancreatic β-cell maintenance and function
Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. Here, the authors show a VGF-derived peptide NERP-4 acts as a positive allosteric modulator on the amino acid transporter SNAT2/SLC38A2, thereby contributing to β-cell maintenance and function.
- Weidong Zhang
- , Ayako Miura
- & Masamitsu Nakazato
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Article
| Open AccessContractile ring mechanosensation and its anillin-dependent tuning during early embryogenesis
Contractile ring formation, positioning, and closure is influenced by tissue mechanics, though how this information is transmitted is unclear. Here they show that Anillin is critical for a mechanosensitive pathway that drives cytokinesis and contractile ring closure.
- Christina Rou Hsu
- , Gaganpreet Sangha
- & Kenji Sugioka
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Article
| Open AccessCharacterization of nucleolar SUMO isopeptidases unveils a general p53-independent checkpoint of impaired ribosome biogenesis
Ribosome biogenesis is tightly coordinated with cell-cycle progression. By characterizing the SUMO isopeptidases SENP3/SENP5, Doenig et al. identify a long-sought p53-independent impaired ribosome checkpoint that converges on downregulation of CDK6.
- Judith Dönig
- , Hannah Mende
- & Stefan Müller
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Article
| Open AccessNutrient deprivation alters the rate of COPII subunit recruitment at ER subdomains to tune secretory protein transport
Movement of secretory cargoes from the endoplasmic reticulum relies on the COPII protein complex. Here, authors combine gene editing technology with state-of-the-art fluorescence microscopy to define the native dynamics of COPII recruitment at ER subdomains for the first time.
- William Kasberg
- , Peter Luong
- & Anjon Audhya
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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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Article
| Open AccessExcess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy
The prion protein PrPC is known to play a role in skeletal muscle development and physiology, including in myopathy. Here, the authors report that excess PrPC binds microRNAs that enhance its aggregation, which inhibits autophagy in muscle cells.
- Jing Tao
- , Yanping Zeng
- & Yi Liang
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Article
| Open AccessPhospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Mitochondria depend on phospholipids supplied by the endoplasmic reticulum. Here, using biochemical assays and molecular dynamics simulations, authors identify VDAC as a scramblase-type lipid transporter that catalyze lipid entry.
- Helene Jahn
- , Ladislav Bartoš
- & Anant K. Menon
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Article
| Open AccessT cell migration requires ion and water influx to regulate actin polymerization
The ability of T cells to migrate is a central component of their functionality and is known to require WNK1 kinase that is linked to the influx of ions into the cell. Here the authors show that T cell migration requires WNK1 mediated ion and water influx to swell the membrane of the leading edge and support actin polymerisation and forward motility.
- Leonard L. de Boer
- , Lesley Vanes
- & Victor L. J. Tybulewicz
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Article
| Open AccessMyeloid cells interact with a subset of thyrocytes to promote their migration and follicle formation through NF-κB
The mechanism underlying thyroid follicle formation is not well understood. Here, the authors show that a subgroup of NF-κB-activated thyrocytes, through interactions with myeloid cells, exhibit increased migration capacity to generate new follicles.
- Yang Rui-Meng
- , Song Shi-Yang
- & Song Huai-Dong
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Article
| Open AccessAtg18 oligomer organization in assembled tubes and on lipid membrane scaffolds
In this work, the authors determined the cryo-EM structures of autophagy-related protein 18 organized in helical tubes and provide insights into the molecular framework for the positioning of downstream components of the autophagy machinery.
- Daniel Mann
- , Simon A. Fromm
- & Carsten Sachse
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Article
| Open AccessThe AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells
Urinary flow is sensed by renal cells but its intensity is dysregulated in renal diseases. Here, the authors report that physiological flow inhibits YAP to promote autophagy, while pathological flow leads to YAP activation and autophagy inhibition.
- Aurore Claude-Taupin
- , Pierre Isnard
- & Nicolas Dupont
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Article
| Open AccessCXCL12 targets the primary cilium cAMP/cGMP ratio to regulate cell polarity during migration
Regulation of cell polarity is key to ensure directed cell migration. Here, Atkins et al. identify the primary cilium cAMP/cGMP ratio as a master regulator of the cell polarity of migrating cortical interneurons downstream of the CXCL12 chemokine.
- Melody Atkins
- , Maud Wurmser
- & Christine Métin
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Article
| Open AccessIntracellular tension sensor reveals mechanical anisotropy of the actin cytoskeleton
Biosensors so far have mostly reported external traction forces exerted against the extracellular matrix or within adhesion receptors. Here, the authors present a sensor that reports molecular tension within the F-actin cytoskeleton.
- Sorosh Amiri
- , Camelia Muresan
- & Michael Murrell
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Article
| Open AccessIdentification of PCPE-2 as the endogenous specific inhibitor of human BMP-1/tolloid-like proteinases
Most proteases have their own endogenous, specific inhibitors which protect living organisms from the deleterious effects of excessive proteolytic activity. Here, authors identify PCPE-2 as a potent and specific inhibitor of BMP-1/tolloid-like proteases.
- Sandrine Vadon-Le Goff
- , Agnès Tessier
- & Catherine Moali
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Article
| Open AccessCytosolic actin isoforms form networks with different rheological properties that indicate specific biological function
β-actin and γ-actin are nearly identical, and yet incorporate into different cytoskeletal structures. Here, the authors create isoform-pure reconstituted networks and study their structural and mechanical differences, underscoring the significance of the isoforms in diverse cellular functions.
- Peter Nietmann
- , Kevin Kaub
- & Andreas Janshoff
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Article
| Open AccessSelenoprotein deficiency disorder predisposes to aortic aneurysm formation
Aortic aneurysms have a heritable basis. Here, the authors report that a selenoprotein deficiency disorder due to mutations in SECISBP2, causes oxidative stress-mediated aortic cell death, predisposing to thoracic aortic aneurysm formation.
- Erik Schoenmakers
- , Federica Marelli
- & Krishna Chatterjee
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Article
| Open AccessDefining a core configuration for human centromeres during mitosis
The detailed 3D organization of human centromere components is unknown. Here, the authors use super-resolution microscopy to present a working model for a common core centromere structure.
- Ayantika Sen Gupta
- , Chris Seidel
- & Jennifer L. Gerton
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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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Matters Arising
| Open AccessHow carvedilol does not activate β2-adrenoceptors
- Robert J. Lefkowitz
- , Howard A. Rockman
- & Milton Packer
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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 AccessiU-ExM: nanoscopy of organelles and tissues with iterative ultrastructure expansion microscopy
Current expansion microscopy approaches need further optimization to achieve the precision of nanoscopy techniques. Here, the authors develop an iterative ultrastructure expansion microscopy (iU-ExM) approach that achieves SMLM-level resolution.
- Vincent Louvel
- , Romuald Haase
- & Paul Guichard
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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 AccessCaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection
Here the authors show that the calcium-sensing kinase CaMKK2 phosphorylates STN1 in response to replication stress and elevated cytosolic calcium concentration to protect stalled replication forks from aberrant MRE11 degradation. Cancer-associated STN1 mutations abolish STN1 phosphorylation, resulting in fork instability.
- Rishi Kumar Jaiswal
- , Kai-Hang Lei
- & Weihang Chai
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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 AccessArabidopsis telomerase takes off by uncoupling enzyme activity from telomere length maintenance in space
Telomeres are proposed to be sentinels for stress. Here, the authors report a strong induction of telomerase in space-flown Arabidopsis without telomere length changes. Instead, telomerase activity is inversely correlated with genome oxidation
- Borja Barbero Barcenilla
- , Alexander D. Meyers
- & Dorothy E. Shippen
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Article
| Open AccessTime-resolved proteomic profiling reveals compositional and functional transitions across the stress granule life cycle
Stress granules (SGs) are dynamic compartments with a poorly characterized transition in composition and function during prolonged stress. In this study, the authors investigated the dynamic changes in SG constituents during acute to prolonged heat shock using time-resolved proteomic profiling.
- Shuyao Hu
- , Yufeng Zhang
- & Yun Bai
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Article
| Open AccessModulation of insulin secretion by RBFOX2-mediated alternative splicing
Insulin secretion from the pancreatic beta cell is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Here, the authors show that the RNA binding protein RBFOX2 is a regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis.
- Nicole D. Moss
- , Kristen L. Wells
- & Lori Sussel
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Article
| Open AccessAcetyl-CoA is a key molecule for nephron progenitor cell pool maintenance
Cell metabolism plays pivotal roles during kidney embryogenesis. This research shows that glycolysis modulation affects nephron progenitor cells via Acetyl-CoA-modulated pathways, influencing both kidney development, and nephron endowment at birth.
- Fabiola Diniz
- , Nguyen Yen Nhi Ngo
- & Giovane G. Tortelote
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Article
| Open AccessDynamical control enables the formation of demixed biomolecular condensates
In this work, the authors report that protein-RNA condensates with shared proteins and distinct RNAs can form and persist in vitro and in cells as distinct entities if the nonshared RNA molecules are dynamically arrested, but the shared protein components are dynamically exchangeable.
- Andrew Z. Lin
- , Kiersten M. Ruff
- & Rohit V. Pappu
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Article
| Open Access3D bioprinted multilayered cerebrovascular conduits to study cancer extravasation mechanism related with vascular geometry
Geometrical complexities of blood vessels alter biophysical behaviors of circulating tumor cells, influencing cancer metastasis. Here, the authors develop a 3D bioprinted in vitro brain blood vessel-on-a-chip to investigate continuities between vascular geometry and metastatic cancer development.
- Wonbin Park
- , Jae-Seong Lee
- & Dong-Woo Cho
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Article
| Open AccessGenetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities
Homologous recombination (HR) gene mutations are thought to be synthetic lethal with DNA polymerase theta (Polθ) inhibition. Here, the authors reveal that Polθ addiction is determined by the functional impact of gene mutations on DNA end resection activity.
- John J. Krais
- , David J. Glass
- & Neil Johnson
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Article
| Open AccessBioE3 identifies specific substrates of ubiquitin E3 ligases
Here, the authors describe BioE3, a biotin-based method to discriminate direct substrates of ubiquitin E3 ligases of interest from mere interactors using proximity proteomics. BioE3 responds to chemical treatments, and works with RING- and HECT-type E3s, as well as ubiquitin-likes (e.g., SUMO).
- Orhi Barroso-Gomila
- , Laura Merino-Cacho
- & James D. Sutherland
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