Featured
-
-
Article
| Open Access
Competence for neural crest induction is controlled by hydrostatic pressure through Yap
Alasaadi et al. report the role of hydrostatic pressure in regulating embryonic competence in the developing neural crest.
- Delan N. Alasaadi
- , Lucas Alvizi
- & Roberto Mayor
-
Article
| Open Access
p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson–Gilford progeria syndrome
Son et al. show that AMPK- and PP2A-dependent p300 nucleocytoplasmic shuttling regulates mTORC1 activity in response to nutrient status. Models of Hutchinson–Gilford progeria syndrome display increased cytoplasmic p300 and mTORC1 hyperactivation.
- Sung Min Son
- , So Jung Park
- & David C. Rubinsztein
-
Article |
Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders
Wang, Chen et al. describe cGAS–STING pathway overactivation in neurons in models of lysosome storage disorders (LSDs). Inactivation of neuronal cGAS–STING signalling alleviates neurodegeneration, suggesting a unifying mechanism mediating LSD pathogenesis.
- Ailian Wang
- , Chen Chen
- & Pinglong Xu
-
News & Views |
FUS maintains TAZ fluidity and function
The transcriptional coactivators TAZ and YAP pair with transcriptional enhanced associate domains (TEADs) to regulate transcription. TAZ and YAP nuclear condensates ensure optimal transcription. A new study reports that FUS regulates TAZ condensates by maintaining them in a fluid state to drive transcription of target genes.
- Wanjin Hong
-
Article |
A chaperone-like function of FUS ensures TAZ condensate dynamics and transcriptional activation
Shao et al. report that FUS interacts with the transcriptional coactivator TAZ, maintaining liquid-like properties of TAZ biomolecular condensates and enhancing TAZ transcriptional activity.
- Yangqing Shao
- , Xin Shu
- & Huasong Lu
-
Article |
O-GlcNAcylation determines the translational regulation and phase separation of YTHDF proteins
Chen et al. report that the YTHDF family of m6A-RNA-binding proteins can be differentially regulated by the post-translational modification O-GlcNAcylation, leading to differential regulation of the YTHDF proteins on translation and phase separation.
- Yulin Chen
- , Ruixi Wan
- & Shixian Lin
-
Article |
A Legionella toxin exhibits tRNA mimicry and glycosyl transferase activity to target the translation machinery and trigger a ribotoxic stress response
Subramanian et al. show that the secreted Legionella protein SidI is a tRNA mimic and glycosyltransferase. SidI inhibits host cell translation by mannosylating ribosomes to induce ribosome collisions and trigger the ribotoxic stress response.
- Advait Subramanian
- , Lan Wang
- & Shaeri Mukherjee
-
Article
| Open Access
A MEC-2/stomatin condensate liquid-to-solid phase transition controls neuronal mechanotransduction during touch sensing
Sanfeliu-Cerdán et al. show that an SH3-domain-induced rigidity transition of MEC-2/stomatin condensates enables mechanotranduction of external forces in C. elegans touch receptor neurons.
- Neus Sanfeliu-Cerdán
- , Frederic Català-Castro
- & Michael Krieg
-
Comment |
A guide to studying mitochondria transfer
Mitochondria can shuttle between adjacent cells or travel to distant organs by breaking away from the parent cell and entering the circulation. Here, we briefly review the state of research into mitochondria transfer, and discuss a methodological framework for studying the process.
- Snigdha Tiash
- , Jonathan Robert Brestoff
- & Clair Crewe
-
Article |
Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis
Qu et al. identify and characterize reciprocal crosstalk between small-cell lung cancer cells and astrocytes, which mimics neuron–astrocyte interactions during brain development and promotes brain metastasis.
- Fangfei Qu
- , Siqi C. Brough
- & Julien Sage
-
Review Article |
Balancing lysosome abundance in health and disease
The mechanisms controlling lysosome abundance in cells and how changes in lysosome pool size impact physiological and pathophysiological processes are discussed.
- Anders P. Mutvei
- , Michal J. Nagiec
- & John Blenis
-
Research Briefing |
Malonyl-CoA links lipid metabolism to nutrient signalling by directly inhibiting mTORC1
Cells use various metabolic pathways to synthesize the building blocks for growth and proliferation. To ensure balanced growth, these biosynthetic processes must be tightly coordinated. We describe a molecular machinery that senses the cellular capacity to make lipids to regulate other biosynthetic processes — such as protein synthesis — accordingly.
-
Article
| Open Access
Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor
Nicastro, Brohée et al. find that the fatty acid synthesis intermediate malonyl-CoA inhibits mTORC1, showing mTORC1 senses the capacity of a cell to synthesise fatty acids and linking fatty acid generation with the overall biosynthetic output through mTORC1.
- Raffaele Nicastro
- , Laura Brohée
- & Constantinos Demetriades
-
Research Briefing |
Nuclear class 3 PI3K coactivates circadian clock
Class 3 phosphatidylinositol-3-kinase (PI3K) has a surprising nuclear function as a coactivator of the circadian clock Bmal1–Clock transcription factor complex for rhythmic purine nucleotide metabolism. This finding opens new avenues for establishing the roles of nuclear subunits of class 3 PI3K in metabolic homeostasis.
-
Article
| Open Access
Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis
Alkhoury et al. show that the class 3 phosphatidylinositol-3-kinase Vps15 subunit coactivates the circadian clock transcription factor Bmal1–Clock for metabolic rhythmicity in the liver and promotes pro-anabolic de novo purine synthesis.
- Chantal Alkhoury
- , Nathaniel F. Henneman
- & Ganna Panasyuk
-
News & Views |
Hypoxia-stabilized RIPK1 promotes cell death
The PHD–pVHL pathway is essential for oxygen-dependent prolyl hydroxylation of HIFA. A recent study identifies RIPK1 as a hydroxylation target in this pathway during hypoxia-induced cell death and presents a 2.8 Å resolution crystal structure of the pVHL–elongin B/C complex bound to hydroxylated RIPK1.
- Wei Ruan
- , Holger K. Eltzschig
- & Xiaoyi Yuan
-
Article |
Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation
Zhang, Xu, Liu, Wang et al. identify an inhibitory mechanism for RIPK1 kinase through EGLN1/pVHL-mediated proline hydroxylation, which is disrupted upon prolonged hypoxia that activates RIPK1 activity to promote cell death and inflammation.
- Tao Zhang
- , Daichao Xu
- & Wenyi Wei
-
Article
| Open Access
mTORC2–NDRG1–CDC42 axis couples fasting to mitochondrial fission
Martinez-Lopez et al. show that fasting or lipid availability stimulates mTORC2 activity in the liver, leading to phosphorylation of NDRG1 and NDRG1–CDC42-mediated mitochondrial fission.
- Nuria Martinez-Lopez
- , Pamela Mattar
- & Rajat Singh
-
News & Views |
A guide from the stomach to β cells
Direct conversions offer an alternative approach to generate insulin-producing cells for cell therapy in diabetes. A study reports a method to convert human stomach-derived gastric stem cells into functional insulin-producing cells through a unique differentiation path.
- Jinhyuk Choi
- , Fritz Cayabyab
- & Eiji Yoshihara
-
News & Views |
A new cell in an old tactile sensory organ
In adult Drosophila, the sense of touch is mediated by mechanosensory organs, namely tactile bristles in the epidermis. A new study reveals that a previously unknown type of epidermal cell, named the F-cell, is recruited to ensheath the tactile bristle and is required for touch sensing.
- Ruijun Zhu
- & Yuh Nung Jan
-
Article |
Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing
Yan et al. harness genome-wide CRISPR screens and identify ILF3 as a signalling intermediate negatively regulating mTORC1 activation upon amino acid sensing. ILF3 recruits GATOR2 to tether the GATOR complexes to lysosomes and regulate mTORC1 activity.
- Guokai Yan
- , Jinxin Yang
- & Ying Liu
-
Article |
A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes
Rubio-Navarro et al. identify a subset of pancreatic beta cells marked by high CD63 levels with enhanced glucose-stimulated insulin secretion. CD63-high beta cells are diminished in mouse models of and in humans with type 2 diabetes.
- Alfonso Rubio-Navarro
- , Nicolás Gómez-Banoy
- & James C. Lo
-
Article |
STAM and Hrs interact sequentially with IFN-α Receptor to control spatiotemporal JAK–STAT endosomal activation
Zanin, Viaris de Lesegno et al. identify what controls the endosomal activation of the IFNAR receptor by IFN-α and establish a central role for endosomal sorting via STAM and Hrs in the differential regulation of JAK–STAT signalling by IFN-α and IFN-β.
- Natacha Zanin
- , Christine Viaris de Lesegno
- & Christophe Lamaze
-
Article |
Nucleus-exported CLOCK acetylates PRPS to promote de novo nucleotide synthesis and liver tumour growth
Liu et al. demonstrate that CK2 phosphorylates CLOCK to promote its nuclear exportation and cytosolic accumulation, thereby acetylating and stabilizing PRPS1/2 and enhancing de novo nucleotide synthesis to facilitate liver tumour growth.
- Tong Liu
- , Zheng Wang
- & Daqian Xu
-
Article |
Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth
Using somatic genome editing and Tuba-seq, Tang et al. uncover a previously uncharacterized role for HRAS and NRAS in impairing KRAS–KRAS interaction to suppress lung tumour growth.
- Rui Tang
- , Emily G. Shuldiner
- & Monte M. Winslow
-
Article |
Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling
Kwak et al. report that adherens junctions organize membrane microdomains, leading to lipid-dependent γ-secretase recruitment and size-dependent protein segregation, excluding full-length Notch receptor.
- Minsuk Kwak
- , Kaden M. Southard
- & Young-wook Jun
-
News & Views |
Metabolic phosphatase moonlights for proteins
In tumours, cancer cells can overcome energy stress via differential regulation of non-canonical ‘moonlighting’ functions of metabolic enzymes. A study now shows that the metabolic phosphatase fructose-1,6-bisphosphatase 1 (FBP1) can act as a nuclear protein phosphatase and reveals how this process is inhibited in cancer cells.
- Scott A. Gerber
- & Arminja N. Kettenbach
-
Article |
Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARα-regulated gene transcription and tumour growth
Wang and colleagues identify a protein phosphatase role for the metabolic enzyme fructose-1,6-bisphosphatase 1 that, upon phosphorylation by PERK, dephosphorylates histone H3 and modulates PPARα-mediated gene expression to inhibit liver cancer progression.
- Zheng Wang
- , Min Li
- & Zhimin Lu
-
Article |
Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration
Banerjee et al. detail the spatial and temporal dynamics of the surface charge on the inner leaflet of the plasma membrane and show that these dynamics are necessary and sufficient to regulate signalling pathways mediating cell migration and polarity.
- Tatsat Banerjee
- , Debojyoti Biswas
- & Peter N. Devreotes
-
Article |
Single-cell atlas of human liver development reveals pathways directing hepatic cell fates
Wesley et al. describe the developmental trajectories of human foetal liver cell types at single-cell resolution and generate bipotential hepatoblast organoids, which can serve as a new platform to investigate human liver development.
- Brandon T. Wesley
- , Alexander D. B. Ross
- & Ludovic Vallier
-
News & Views |
Keeping up with the Rag GTPases
The Rag GTPases form the link between extracellular nutrients and the activation of mTORC1. RagA/B and RagC/D have been considered functionally redundant, but two studies now show that each isoform and gene have specific features, making their control of mTORC1 activity more nuanced and complex than previously appreciated.
- Nicola Alesi
- & Elizabeth P. Henske
-
Article
| Open Access
A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids
Gollwitzer, Grützmacher et al. and Figlia et al. establish that the various Rag GTPase genes and isoforms differentially regulate mTORC1 activity and distinctly modulate the responsiveness of mammalian cells to amino acid availability.
- Peter Gollwitzer
- , Nina Grützmacher
- & Constantinos Demetriades
-
Article
| Open Access
Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition
Gollwitzer et al. and Figlia et al. establish that the different Rag GTPase genes and isoforms differentially regulate mTORC1 activity and distinctly modulate the responsiveness of mammalian cells to amino acid availability.
- Gianluca Figlia
- , Sandra Müller
- & Aurelio A. Teleman
-
Article |
NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling
Verma et al. demonstrate that GCDH depletion in melanoma cells induces NRF2 glutarylation, upregulates ATF4 and ATF3 signalling and promotes cell death, thereby suppressing tumour growth.
- Sachin Verma
- , David Crawford
- & Ze’ev A. Ronai
-
News & Views |
EGFR ligands dictate tumour suppression
EGFR is an oncogene that is frequently amplified in glioblastoma. A new study suggests a tumour-suppressive role of EGFR in EGFR-amplified glioblastoma regulated by ligand abundance. Increased EGFR ligand in EGFR-amplified glioblastoma suppresses invasion by upregulating BIN3 and inhibiting activation of Rho GTPases.
- Mary Clare Beytagh
- & William A. Weiss
-
Article |
EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation
Guo et al. show that ligand-induced EGFR activation suppresses invasion by upregulating BIN3 and inhibiting DOCK7-regulated Rho GTPase activity in EGFR-amplified glioblastoma, which is in contrast to the known oncogenic role for EGFR signalling.
- Gao Guo
- , Ke Gong
- & Amyn A. Habib
-
Article |
The spectrin cytoskeleton integrates endothelial mechanoresponses
Mylvaganam et al. report that an apical spectrin network in endothelial cells can transmit mechanical forces in response to shear flow-induced stress, requiring hyaluronic acid and involving PIEZO1.
- Sivakami Mylvaganam
- , Jonathan Plumb
- & Sergio Grinstein
-
Article |
A p53–phosphoinositide signalosome regulates nuclear AKT activation
Chen et al. report that following genotoxic stress, a nuclear PI3K binds p53 to generate a p53–phosphoinositide signalosome that recruits AKT and its activators, resulting in nuclear AKT activation and cell survival.
- Mo Chen
- , Suyong Choi
- & Richard A. Anderson
-
Article |
THY1-mediated mechanisms converge to drive YAP activation in skin homeostasis and repair
Sedov et al. report that THY1 regulates cell–matrix and cell–cell interactions to orchestrate YAP activity during skin homeostasis and regeneration.
- Egor Sedov
- , Elle Koren
- & Yaron Fuchs
-
News & Views |
Intrinsically disordered CO2 sensors
Intrinsically disordered regions are a ubiquitous class of protein domains that lack a fixed 3D structure. Here, an evolutionarily conserved family of disordered CO2 sensors has been discovered, expanding the growing repertoire of disordered regions that respond to changes in the cellular environment.
- Ryan J. Emenecker
- & Alex S. Holehouse
-
Article
| Open Access
Actin remodelling controls proteasome homeostasis upon stress
Williams et al. report that, upon TORC1 inhibition in yeast, mRNA of the chaperone protein ADC17 is localized to cortical actin patches where its translation is enhanced upon stress.
- Thomas David Williams
- , Roberta Cacioppo
- & Adrien Rousseau
-
Letter |
Ceramide-rich microdomains facilitate nuclear envelope budding for non-conventional exosome formation
Arya et al. identify a pathway for exosome generation in immune cells that originates at the nuclear envelope and is facilitated by nSMase1-mediated generation of ceramide.
- Subhash B. Arya
- , Song Chen
- & Carole A. Parent
-
Letter |
The intrinsically disordered region from PP2C phosphatases functions as a conserved CO2 sensor
Zhang et al. identify that a group of PP2C phosphatases is responsible for direct sensing of CO2 in the environment via phase separation of an intrinsically disordered region, which is a conserved mechanism across various species.
- Mao Zhang
- , Cheng Zhu
- & Yang Lu
-
News & Views |
Stress response regulates cancer fibroblasts
Fibroblasts become activated during wound repair and rapidly return to a ‘resting’ state, and are thus critical for normal tissue homeostasis and tumour development. A new study now reveals an important pro-tumorigenic role for the stress response in cancer-associated fibroblasts that may offer a new opportunity to limit tumour progression.
- Douglas V. Faget
- & Sheila A. Stewart
-
Article
| Open Access
A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression
Verginadis et al. show that ATF4 regulates Col1a1 expression and collagen biosynthesis in perivascular cancer-associated fibroblasts, thereby supporting angiogenesis and progression in melanoma and pancreatic cancer.
- Ioannis I. Verginadis
- , Harris Avgousti
- & Constantinos Koumenis
-
Article |
Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth
Cao et al. show that miR-122 encapsulated in breast cancer-derived extracellular vesicles targets PKM to downregulate β-cell insulin secretion, leading to dysregulated glucose homeostasis and enhanced tumour growth.
- Minghui Cao
- , Roi Isaac
- & Shizhen Emily Wang
-
News & Views |
Defining the pathways of heart regeneration
Although cardiac cell therapy has been intensely studied, the high expectations are still an unmet goal. A study now characterizes the translational potential and mode of action of human ventricular progenitors (HVPs) derived from embryonic stem cells, as a source for cardiac cell therapy.
- Louk Theodoor Timmer
- & Eva van Rooij
-
Article
| Open Access
Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors
In this study, the authors report that pluripotent stem cell-derived ventricular progenitors target loss of myocardium and fibrotic scarring to promote heart regeneration, thus offering new potential therapeutic strategies for heart injury.
- Christine M. Poch
- , Kylie S. Foo
- & Karl-Ludwig Laugwitz
-
News & Views |
Phosphoinositide phosphorylation sans kinase
Phosphoinositide signalling regulates cellular processes and is hijacked by pathogens. Classically, phosphoinositides are produced by kinase- and phosphatase-catalysed reactions. A study now reveals an unprecedented, kinase- and ATP-free synthesis of PtdIns(3,4)P2 via a phosphotransferase mechanism during bacterial infection.
- Xiaofu Cao
- & Jeremy M. Baskin
Mammalian IRE1α dynamically and functionally coalesces with stress granules