Featured
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Research Briefing |
Regulation of mitochondrial fission by fatty acyl-coenzyme A
We show that the mitochondrial fission proteins MiD49 and MiD51 are activated by fatty acyl-coenzyme A (FA-CoA). FA-CoA binds in a previously identified pocket located within MiDs, inducing their oligomerization and ability to activate the dynamin DRP1, ultimately promoting mitochondrial fission. Activated MiDs synergize with mitochondrial fission factor (MFF) in stimulating DRP1 activity, leading us to hypothesize that MiDs act upstream of MFF during mitochondrial fission.
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News & Views |
Adding a transcription-coupled repair pathway
When transcription by RNA polymerase II is stalled by ultraviolet-induced DNA damage, it recruits repair factors, leading to excision of the damaged site and DNA synthesis to fill the gap. Three new studies show that, for aldehyde-induced DNA crosslinks, repair is activated by the same factors, but without base excision and gap filling.
- Marco Saponaro
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Article |
Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51
Liu et al. find that long-chain acyl-coenzyme A activates two mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization. This activates their ability to stimulate DRP1 GTPase activity and triggers mitochondrial division.
- Ao Liu
- , Frieda Kage
- & Henry N. Higgs
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Resource |
A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility
Morgan, Pernes and colleagues perform mass spectrometry-based targeted lipidomics and provide a comprehensive lipid profile of human and mouse immune cells, which they then show confer differential ferroptosis susceptibilities.
- Pooranee K. Morgan
- , Gerard Pernes
- & Andrew J. Murphy
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News & Views |
Mesoscale condensates organize the cytoplasm
Biomolecular condensates are recognized for their ability to compartmentalize the cytoplasm without bounding membranes, but the degree to which they organize the cytoplasm has not been clear. A new study reveals that condensates at a scale of 100 nm are responsible for the organization of at least 18% of the cytoplasmic proteome.
- Leshani Ahangama Liyanage
- & Jonathon A. Ditlev
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Letter |
Evidence for widespread cytoplasmic structuring into mesoscale condensates
Keber et al. use filtration chromatography and quantitative proteomics of Xenopus egg extracts and show that at least 18% of cytoplasmic proteins are organized in small ~100-nm biomolecular condensates.
- Felix C. Keber
- , Thao Nguyen
- & Martin Wühr
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Article
| Open AccessCAMSAPs and nucleation-promoting factors control microtubule release from γ-TuRC
Rai et al. report that CAMSAPs can bind to minus ends of microtubules attached to γ-tubulin ring complex (γ-TuRC) and drive microtubule release. They show that CDK5RAP2, but not CLASP2, inhibits CAMSAP-mediated microtubule release from γ-TuRC.
- Dipti Rai
- , Yinlong Song
- & Anna Akhmanova
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News & Views |
METTL3 restrains autoimmunity in β-cells
Activation of innate immunity has been linked to the progression of type 1 diabetes. A study now shows that overexpression of METTL3, a writer protein of the m6A machinery that modifies mRNA, restrains interferon-stimulated genes when expressed in pancreatic β-cells, identifying it as a promising therapeutic target.
- Balasubramanian Krishnamurthy
- & Helen E. Thomas
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Article |
Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes
De Jesus et al. describe the redox-mediated regulation of m6A writer methyltransferase 3, which blunts innate immune responses by modification of RNA sensor and editor component mRNAs during the onset of type 1 diabetes in β-cells.
- Dario F. De Jesus
- , Zijie Zhang
- & Rohit N. Kulkarni
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Article
| Open AccessDrosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels
Li, Guo, Wang and colleagues show that the ion channels TMEM63 in Drosophila and TMEM63A in mouse mediate lysosomal mechanosensitivity and modulate lysosomal morphology and function.
- Kai Li
- , Yanmeng Guo
- & Yuh Nung Jan
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Article
| Open AccessFOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy
van der Weijden et al. perform genomic, proteomic and metabolic analyses and find that FOXO1-mediated fatty acid oxidation maintains mouse embryos in diapause.
- Vera A. van der Weijden
- , Maximilian Stötzel
- & Aydan Bulut-Karslioglu
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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
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News & Views |
Hijacking host ribosomes via tRNA mimicry
The bacterial pathogen Legionella pneumophila uses effectors — toxins — to facilitate pathogenesis within host cells. A recent study identifies dual mechanisms of the effector SidI as an inhibitor of translation elongation. The N-terminal domain mimics tRNA, whereas the C-terminal domain glycosylates the ribosome.
- Saori Uematsu
- & Shu-Bing Qian
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News & Views |
Saving ribosomal proteins for later
Disruption of ribosome assembly results in the accumulation of aggregation-prone ‘orphaned’ ribosomal proteins that are toxic to cells if left unchecked. A study finds that cells store such ribosomal proteins during heat shock to enable a quick recovery of ribosome assembly after the removal of this stress.
- Joshua J. Black
- & Rachel Green
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Article |
Hem25p is required for mitochondrial IPP transport in fungi
Tai et al. show that Hem25p—a mitochondrial glycine transporter required for haem biosynthesis—is also needed for isopentenyl pyrophosphate (IPP) transport into mitochondria and coenzyme Q synthesis in Saccharomyces cerevisiae.
- Jonathan Tai
- , Rachel M. Guerra
- & David J. Pagliarini
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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.
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Article
| Open AccessMalonyl-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
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Letter |
ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription
Dai et al. show that the transcription factor ATFS-1 interferes with mitochondrial pre-initiation transcription complex assembly and promotes mitochondrial DNA repair, thereby reducing age-dependent mitochondrial DNA damage in Caenorhabditis elegans.
- Chuan-Yang Dai
- , Chai Chee Ng
- & Steven Zuryn
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Article
| Open AccessDynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability
Gaggioli, Lo et al. show that the histone methyltransferase EHMT2/G9a catalyses heterochromatin assembly at stressed replication forks. Untimely heterochromatin disassembly by demethylase KDM3A exposes forks to PRIMPOL-mediated genome instability.
- Vincent Gaggioli
- , Calvin S. Y. Lo
- & Nitika Taneja
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News & Views |
Guiding DNA repair at the nuclear periphery
The nuclear envelope participates in the spatial regulation of DNA repair, but the mechanisms behind this are unclear. A study now reports that a nuclear envelope-localized nuclease, NUMEN/ENDOD1, guides the choice of DNA-repair pathway by inhibiting the resection of DNA ends and aberrant recombination, ensuring genome stability.
- Sylvain Audibert
- & Evi Soutoglou
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Article |
Delivery of low-density lipoprotein from endocytic carriers to mitochondria supports steroidogenesis
Zhou et al. describe an intracellular transport pathway of low-density lipoprotein (LDL)–LDL receptor from the plasma membrane that bypasses lysosomes and delivers cholesterol to mitochondria for steroidogenesis.
- Yu-Xia Zhou
- , Jian Wei
- & Jie Luo
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News & Views |
Nonmetabolic role for CKB in ferroptosis
The selenoprotein glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, a form of cell death earmarked by unrestrained lipid peroxidation. A new study shows that the metabolic enzyme creatinine kinase B (CKB) phosphorylates GPX4, which may influence the susceptibility of cancer cells to ferroptosis.
- Eikan Mishima
- & Marcus Conrad
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Article |
Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function
Wu et al. show that, upon activation by insulin-like growth factor 1 receptor and AKT, creatine kinase B exhibits a moonlighting function as protein kinase to phosphorylate glutathione peroxidase 4 to prevent its degradation, thereby suppressing ferroptosis and enhancing tumour growth in mice.
- Ke Wu
- , Meisi Yan
- & Daqian Xu
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News & Views |
Mediterranean mechanisms of longevity
The Mediterranean diet correlates with increased human lifespan; it is rich in foods with high levels of cis-monounsaturated fatty acids (MUFAs), such as olive oil. A study now shows that MUFAs stimulate a lipid droplet–peroxisome organelle network to decrease lipid oxidation and protect cell membranes during ageing.
- Alexander Richard Mendenhall
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Technical Report
| Open AccessMetaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns
Berg et al. describe Metaboverse, a tool for automated discovery and visualization of metabolic data. Metaboverse enhances the user’s ability to extract meaningful patterns from multi-omics datasets to describe metabolic responses and signatures.
- Jordan A. Berg
- , Youjia Zhou
- & Jared Rutter
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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
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Technical Report |
A general approach to identify cell-permeable and synthetic anti-CRISPR small molecules
Lim et al. developed a fluorescence resonance energy transfer-based assay to identify anti-CRISPR molecules and discovered an SpCas9 inhibitor that is twofold more efficient in inhibiting Cas9 at diverse genomic loci than existing inhibitors and easy to synthesize.
- Donghyun Lim
- , Qingxuan Zhou
- & Amit Choudhary
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News & Views |
Chaperoning the nuclear envelope
FG-nucleoporins of the nuclear pore complexes form a permeability barrier between the nucleus and the cytosol. FG-nucleoporins contain disordered regions and are prone to aggregation. Two studies identify the chaperone DNAJB6 as a key factor that prevents aggregation of FG-nucleoporins and assists in the biogenesis of nuclear pore complexes.
- Janine Kirstein
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Article |
Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities
Kuiper et al. and Prophet et al. implicate DNAJB6/HSP70 chaperone activities in the biogenesis of the nuclear pore complex permeability barrier and find that disease-linked nuclear envelope blebs are enriched in nucleoporin and chaperone condensates.
- Sarah M. Prophet
- , Anthony J. Rampello
- & Christian Schlieker
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Article |
Elongator stabilizes microtubules to control central spindle asymmetry and polarized trafficking of cell fate determinants
Planelles-Herrero et al. identify a function for the Elongator complex independent of its enzymatic activity in controlling microtubule stability and generating central spindle asymmetry during asymmetric division in Drosophila.
- Vicente Jose Planelles-Herrero
- , Alice Bittleston
- & Emmanuel Derivery
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Letter |
The chaperone DNAJB6 surveils FG-nucleoporins and is required for interphase nuclear pore complex biogenesis
Kuiper et al. and Prophet et al. implicate DNAJB6/HSP70 chaperone activities in the biogenesis of the nuclear pore complex permeability barrier and find that disease-linked nuclear envelope blebs are enriched in nucleoporin and chaperone condensates.
- E. F. Elsiena Kuiper
- , Paola Gallardo
- & Steven Bergink
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Comment |
Quick tips for re-using metabolomics data
Publicly shared metabolomics data may contain key answers to central questions in cell biology, but re-use of the data is complicated by the lack of standardized experimental and computational methods in the field. This Comment provides some tips to help ensure that shared metabolomics data are re-used appropriately.
- Ethan Stancliffe
- & Gary J. Patti
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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
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News & Views |
Finding a chaperone for TDP-43
Aggregation of the RNA-binding protein TDP-43 is commonly observed in neurodegenerative disorders. A new study reveals that this process may be blocked by HSPB1, a small heat shock protein that can also regulate TDP-43 phase separation. This may be relevant to neurodegeneration, as loss of HSPB1 correlates with TDP-43 pathology.
- Yuna M. Ayala
- & Zachary R. Grese
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Article
| Open AccessIdentification of two pathways mediating protein targeting from ER to lipid droplets
Song et al. identify two protein-targeting pathways from the endoplasmic reticulum to (1) early lipid droplets (LDs) and (2) mature lipid droplets. They define key factors mediating the second, late pathway and its many cargoes.
- Jiunn Song
- , Arda Mizrak
- & Tobias C. Walther
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News & Views |
Navigating ferroptosis via an NADPH sensor
NADPH levels serve as a biomarker of sensitivity to ferroptosis, but the regulators that detect cellular NADPH levels and modulate downstream ferroptosis responses are unknown. A study now identifies MARCHF6 in the ubiquitin system as an NADPH sensor that suppresses ferroptosis.
- Chao Mao
- & Boyi Gan
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Article |
The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis
Nguyen et al. show that the E3 ubiquitin ligase MARCHF6 acts as an NADPH sensor to suppress ferroptosis. Mechanistically, NADPH binds to MARCHF6 and activates its E3 ligase activity, enhancing the degradation of pro-ferroptosis proteins.
- Kha The Nguyen
- , Sang-Hyeon Mun
- & Cheol-Sang Hwang
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Article
| Open AccessNucleotide imbalance decouples cell growth from cell proliferation
Diehl et al. show that imbalance among nucleotide species is not sensed by canonical metabolic regulatory pathways, causing excessive cell growth despite a DNA replication block. ATR is needed to increase nucleotide availability in normal S phase.
- Frances F. Diehl
- , Teemu P. Miettinen
- & Matthew G. Vander Heiden
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Letter |
ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16INK4a levels
Hao et al. describe an RNA-editing-independent role for ADAR1 in driving senescence. Autophagy downregulates ADAR1 in aged tissues, decreasing the binding of ADAR1 partner HuR to target mRNAs, including SIRT1. Loss of SIRT1 enhances p16INK4a levels.
- Xue Hao
- , Yusuke Shiromoto
- & Rugang Zhang
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News & Views |
A kinesin mimics DNA
Primary cilia transduce cues, including Hedgehog (Hh) signals, and possess doublet microtubules that interact with kinesin motors. The kinesin KIF7 is important for Hh signalling and binds to GLI transcription factors. Haque et al. reveal that, surprisingly, GLI proteins bind a DNA-like part of KIF7 to promote their accumulation at the ciliary tip.
- Dhivya Kumar
- & Jeremy F. Reiter
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World View |
The case to be proud as an LGBTQIA+ scientist
Pride holds a special place in the hearts of lesbian, gay, bisexual, transgender, queer, intersex, asexual+ (LGBTQIA+) individuals as a time to celebrate the progress we have made, and advocate for the advances yet to come. Here, I highlight ways in which the scientific community has had a crucial role in driving this progress, and provide a personal perspective on the importance of being open and proud of my identity as a gay cell biologist.
- Yee-Hung Mark Chan
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Article |
Cytoskeletal regulation of a transcription factor by DNA mimicry via coiled-coil interactions
Haque et al. report that the Hedgehog pathway kinesin KIF7 binds the transcription factor GLI via electrostatic coiled-coil interactions, and synergy between KIF7 and GLI underlies the recruitment of both proteins to microtubules and the cilium tip.
- Farah Haque
- , Christian Freniere
- & Radhika Subramanian
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News & Views |
Long life depends on open communication
The lysosome is an essential organelle that degrades extra- and intra-cellular components and acts as a signaling hub. A study in Caenorhabditis elegans now shows that the lysosome mediates inter-tissue communication from periphery to neurons to regulate lifespan via fatty acid breakdown and secretion.
- Jason Wayne Miklas
- & Anne Brunet
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Article
| Open AccessLysosome lipid signalling from the periphery to neurons regulates longevity
Savini et al. report that lysosomal lipolysis in peripheral adipose depots produces polyunsaturated fatty acids (PUFAs). PUFAs and the lipid chaperone LBP-3 induce a nuclear hormone receptor, neuropeptide-mediated cascade in neurons to extend lifespan.
- Marzia Savini
- , Andrew Folick
- & Meng C. Wang
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Technical Report
| Open AccessMETALIC reveals interorganelle lipid flux in live cells by enzymatic mass tagging
John Peter et al. develop METALIC (Mass tagging-Enabled TrAcking of Lipids In Cells), an approach to track interorganelle lipid flux in live cells using organelle-targeted enzymatic labelling of lipid subpopulations and mass spectrometry.
- Arun T. John Peter
- , Carmelina Petrungaro
- & Benoît Kornmann
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Letter |
Assembly of Tetraspanin-enriched macrodomains contains membrane damage to facilitate repair
Huang et al. report that Tetraspanin proteins assemble a rigid ring structure around the damaged plasma membrane to prevent the wound from expanding, thus facilitating membrane repair by the ESCRT machinery and other repair factors.16:58
- Yuwei Huang
- , Xing Zhang
- & Li Yu
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Article
| Open AccessProton-gated anion transport governs macropinosome shrinkage
Zeziulia et al. identify the proton-activated Cl− channel ASOR/TMEM206 as necessary for shrinkage of macropinosomes, which is needed for downstream sorting events.
- Mariia Zeziulia
- , Sandy Blin
- & Thomas J. Jentsch
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Perspective |
Substoichiometric action of long noncoding RNAs
Unfried and Ulitsky discuss recent advances in understanding how long noncoding RNAs expressed at much lower levels compared with their targets or cofactors overcome the stoichiometric disadvantages and exert their cellular functions.
- Juan Pablo Unfried
- & Igor Ulitsky
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Article |
ETV2 functions as a pioneer factor to regulate and reprogram the endothelial lineage
Gong et al. report that ETV2 functions as a pioneer factor that remodels chromatin and regulates endothelial genes, thus providing a mechanism of endothelial development with potential therapeutic applications.
- Wuming Gong
- , Satyabrata Das
- & Daniel J. Garry
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