Featured
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Genetic risk converges on regulatory networks mediating early type 2 diabetes
Integration of multiomics data with functional analysis of pancreatic tissues from individuals with early-stage type 2 diabetes indicates that the genetic risk converges on RFX6, which regulates chromatin architecture at multiple risk loci.
- John T. Walker
- , Diane C. Saunders
- & Marcela Brissova
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Perspective |
The power and potential of mitochondria transfer
The mechanisms by which mitochondria are transferred between cells and how intercellular mitochondria transfer regulates physiological processes and disease pathogenesis are discussed.
- Nicholas Borcherding
- & Jonathan R. Brestoff
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Article
| Open Access
An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption
Haemoglobin produced by chondrocytes forms eosin-positive haemoglobin bodies in their cytoplasm, and deletion of these bodies causes severe hypoxia.
- Feng Zhang
- , Bo Zhang
- & Qiang Sun
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Article
| Open Access
Transgenic ferret models define pulmonary ionocyte diversity and function
Conditional genetic ferret models enable ionocyte lineage tracing, ionocyte ablation and ionocyte-specific deletion of CFTR to elucidate the roles of pulmonary ionocyte biology and function during human health and disease.
- Feng Yuan
- , Grace N. Gasser
- & John F. Engelhardt
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Article |
Lactate regulates cell cycle by remodelling the anaphase promoting complex
Discovery of a biochemical mechanism through which lactate binds and inhibits the SUMO protease SENP1, stimulating timed degradation of cell cycle proteins, and resulting in mitotic exit.
- Weihai Liu
- , Yun Wang
- & Edward T. Chouchani
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Article
| Open Access
Fumarate induces vesicular release of mtDNA to drive innate immunity
Fumarate metabolism regulates the innate immune response through a mechanism in which high levels of fumarate result in the generation of mitochondrial-derived vesicles and the release of mitochondrial DNA into the cytosol, which activates inflammatory pathways.
- Vincent Zecchini
- , Vincent Paupe
- & Christian Frezza
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Article |
A spatiotemporally resolved single-cell atlas of the Plasmodium liver stage
Single-cell RNA sequencing and single-molecule RNA transcript imaging have been used to characterize spatially and temporally resolved mouse liver and parasite expression programmes during infection with the rodent malaria parasite Plasmodium berghei ANKA.
- Amichay Afriat
- , Vanessa Zuzarte-Luís
- & Shalev Itzkovitz
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Article |
Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes
PD-L1 expression by senescent cells renders them resistant to clearance by CD8 T cells, suggesting PD-L1 as a target for mitigating the effects of ageing.
- Teh-Wei Wang
- , Yoshikazu Johmura
- & Makoto Nakanishi
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Article |
CLN3 is required for the clearance of glycerophosphodiesters from lysosomes
The lysosomal transmembrane protein CLN3 is required for the lysosomal clearance of glycerophosphodiesters in mice and in human cells, suggesting that the loss of CLN3 causes Batten disease in children due to defects in glycerophospholipid metabolism.
- Nouf N. Laqtom
- , Wentao Dong
- & Monther Abu-Remaileh
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Article
| Open Access
Structure of the MRAS–SHOC2–PP1C phosphatase complex
A structure of the MRAS–SHOC2–PP1C complex supports a RAS-driven and multi-molecular model for RAF activation in which individual RAS–GTP molecules recruit RAF–14-3-3 and SHOC2–PP1C to activate the downstream pathway.
- Zachary J. Hauseman
- , Michelle Fodor
- & Daniel A. King
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Article |
GREM1 is required to maintain cellular heterogeneity in pancreatic cancer
The BMP inhibitor GREM1 is a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse.
- Linxiang Lan
- , Theodore Evan
- & Axel Behrens
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Article
| Open Access
Mitochondrial RNA modifications shape metabolic plasticity in metastasis
- Sylvain Delaunay
- , Gloria Pascual
- & Michaela Frye
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Article |
Human distal airways contain a multipotent secretory cell that can regenerate alveoli
Human respiratory bronchioles contain a unique population of secretory cells called respiratory airway secretory cells that are distinct from the cells in the larger proximal airways, and act as unidirectional progenitors for alveolar type 2 cells.
- Maria C. Basil
- , Fabian L. Cardenas-Diaz
- & Edward E. Morrisey
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Article |
A hormone complex of FABP4 and nucleoside kinases regulates islet function
Hormonal FABP4 is discovered to be a pivotal regulator of an adipose–beta-cell endocrine axis that coordinates energy status and metabolic organ function, and targeting this axis improved metabolic outcomes.
- Kacey J. Prentice
- , Jani Saksi
- & Gökhan S. Hotamisligil
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Article |
Herpesviruses assimilate kinesin to produce motorized viral particles
Herpes simplex virus type I and pseudorabies virus assimilate kinesin from host epithelial cells and repurpose the motor to traffic to the nuclei of neurons in the peripheral nervous system.
- Caitlin E. Pegg
- , Sofia V. Zaichick
- & Gregory A. Smith
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Article |
Virus-induced senescence is a driver and therapeutic target in COVID-19
Virus-induced senescence is a central pathogenic feature in COVID-19, and senolytics, which promote apoptosis of senescent cells, can reduce disease severity in hamsters,mice, as well as humans infected with SARS-CoV-2.
- Soyoung Lee
- , Yong Yu
- & Clemens A. Schmitt
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Article |
CRL4AMBRA1 is a master regulator of D-type cyclins
Biochemical and genetics studies identify CRL4AMBRA1 as the ubiquitin ligase that has a key role in regulating the stability of D-type cyclins during cell-cycle progression.
- Daniele Simoneschi
- , Gergely Rona
- & Michele Pagano
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Article |
Chromothripsis drives the evolution of gene amplification in cancer
Chromothripsis—a process during which chromosomes are ‘shattered’—drives the evolution of gene amplification and subsequent drug resistance in cancer cells.
- Ofer Shoshani
- , Simon F. Brunner
- & Don W. Cleveland
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Article |
Macrophage-derived glutamine boosts satellite cells and muscle regeneration
Mouse models of muscle injuries and ageing characterized by low levels of intra-tissue glutamine are ameliorated by macrophage-specific deletion or systemic pharmacological inhibition of glutamate dehydrogenase 1, which results in constitutively high activity of glutamine synthetase.
- Min Shang
- , Federica Cappellesso
- & Massimiliano Mazzone
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Article |
snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis
Single-nucleus RNA sequencing in mouse and human adipose tissue identifies a subpopulation of adipocytes that regulates thermogenesis in neighbouring adipocytes in a paracrine manner by modulating acetate signalling.
- Wenfei Sun
- , Hua Dong
- & Christian Wolfrum
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Article |
Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis
The transient reactivation of ETV2 in adult human endothelial cells reprograms these cells to become adaptable vasculogenic endothelia that in three-dimensional matrices self-assemble into vascular networks that can transport blood and physiologically arborize organoids and decellularized tissues.
- Brisa Palikuqi
- , Duc-Huy T. Nguyen
- & Shahin Rafii
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Article |
IGF1R is an entry receptor for respiratory syncytial virus
Respiratory syncytial virus enters cells by binding to cell-surface IGFR1, which activates PKCζ and induces trafficking of the NCL coreceptor to the RSV particles at the cell surface.
- Cameron D. Griffiths
- , Leanne M. Bilawchuk
- & David J. Marchant
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Article |
Hepatic NADH reductive stress underlies common variation in metabolic traits
The authors identify an increased hepatic NADH/NAD+ ratio as an underlying metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases.
- Russell P. Goodman
- , Andrew L. Markhard
- & Vamsi K. Mootha
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Article |
Proteomics of SARS-CoV-2-infected host cells reveals therapy targets
SARS-CoV-2 modulates central cellular pathways, such as translation, splicing, carbon metabolism, proteostasis and nucleic acid metabolism, in human cells; these pathways can be inhibited by small-molecule inhibitors to prevent viral replication in the cells.
- Denisa Bojkova
- , Kevin Klann
- & Christian Münch
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Article |
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.
- David E. Gordon
- , Gwendolyn M. Jang
- & Nevan J. Krogan
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Article |
LRP1 is a master regulator of tau uptake and spread
Low-density lipoprotein receptor-related protein 1 (LRP1) is shown to be a critical determinant of tau propagation in the brain.
- Jennifer N. Rauch
- , Gabriel Luna
- & Kenneth S. Kosik
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Article |
Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche
Single-cell RNA-sequencing analysis of intestinal mesenchyme identified a population of fibroblasts that produce prostaglandin E2, which, when disrupted, prevented initiation of intestinal tumours.
- Manolis Roulis
- , Aimilios Kaklamanos
- & Richard A. Flavell
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Article |
Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation
Analyses of mouse models of inflammation suggest some chronic inflammatory conditions may result from Z-DNA-binding protein 1 sensing endogenous Z-form nucleic acids—such as those of endogenous retroelements—through its Zα domains.
- Huipeng Jiao
- , Laurens Wachsmuth
- & Manolis Pasparakis
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Article |
The guidance receptor plexin D1 is a mechanosensor in endothelial cells
PLXND1 is a mechanosensor that is required for endothelial cells to respond to shear stress both in vitro and in vivo by regulating the site-specific distribution of atherosclerotic lesions.
- Vedanta Mehta
- , Kar-Lai Pang
- & Ellie Tzima
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Article |
ATP13A2 deficiency disrupts lysosomal polyamine export
The lysosomal polyamine transporter ATP13A2 controls the cellular polyamine content, and impaired lysosomal polyamine export represents a lysosome-dependent cell death pathway that may be implicated in ATP13A2-associated neurodegeneration.
- Sarah van Veen
- , Shaun Martin
- & Peter Vangheluwe
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Article |
Impaired cell fate through gain-of-function mutations in a chromatin reader
The histone-acetylation-reader protein ENL is mutated in a paediatric kidney cancer in such a way that it clusters at target genes, increasing the recruitment of the transcriptional machinery, enhancing transcription and deregulating cell fate during development.
- Liling Wan
- , Shasha Chong
- & C. David Allis
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Article |
Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis
A whole-genome short interfering RNA screen identified vacuolar ATPase as a regulator of macropinocytosis induced by oncogenic RAS, a key determinant of tumour cell growth under nutrient-limiting conditions.
- Craig Ramirez
- , Andrew D. Hauser
- & Dafna Bar-Sagi
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Article |
Regulation of α-synuclein by chaperones in mammalian cells
Chaperones interact with a canonical motif in α-synuclein, which can be prevented by phosphorylation of α-synuclein at Tyr39, whereas inhibition of this interaction leads to the localization of α-synuclein to the mitochondria and aggregate formation.
- Björn M. Burmann
- , Juan A. Gerez
- & Sebastian Hiller
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Article |
Developmental ROS individualizes organismal stress resistance and lifespan
A subpopulation of Caenorhabditis elegans, in which there is a naturally occurring transient increase in reactive oxygen species during early development, exhibits increased stress resistance, improved redox homeostasis and prolonged lifespan, which are linked to a global decrease in level of the histone mark H3K4me3.
- Daphne Bazopoulou
- , Daniela Knoefler
- & Ursula Jakob
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Article |
Patch repair of deep wounds by mobilized fascia
Cells that populate scar tissue in mammalian skin migrate to wounds as prefabricated matrix from the subcutaneous fascia, including embedded blood vessels, macrophages and peripheral nerves.
- Donovan Correa-Gallegos
- , Dongsheng Jiang
- & Yuval Rinkevich
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Article |
The ADP/ATP translocase drives mitophagy independent of nucleotide exchange
A CRISPR–Cas9 genetic screen shows that the adenine nucleotide translocator is required for mitophagy and that this role is independent of its nucleotide translocase activity.
- Atsushi Hoshino
- , Wei-jia Wang
- & Zoltan Arany
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Article |
Resolving the fibrotic niche of human liver cirrhosis at single-cell level
Single-cell RNA sequencing is used to characterize and compare the functional diversity of cells from liver biopsies of human scarred and normal liver, and identifies markers for scar-associated macrophages and endothelial cells.
- P. Ramachandran
- , R. Dobie
- & N. C. Henderson
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Letter |
The RIPK4–IRF6 signalling axis safeguards epidermal differentiation and barrier function
Signalling between the transcription factor IRF6 and the kinase RIPK4, in particular the phosphorylation of IRF6 by RIPK4, regulates epidermal differentiation and lipid metabolism, thereby maintaining the function of the epidermal barrier.
- Nina Oberbeck
- , Victoria C. Pham
- & Vishva M. Dixit
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Review Article |
From discoveries in ageing research to therapeutics for healthy ageing
The milestones that mark the advances in ageing research, the medical, commercial and societal implications of ageing and the different ageing pathways and processes that are associated with ageing are discussed.
- Judith Campisi
- , Pankaj Kapahi
- & Eric Verdin
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Letter |
FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes
Mutations in the transcription factor FOXA1 that are common in prostate cancer result in gain-of-function effects that promote changes in the differentiation of tumour cells.
- Elizabeth J. Adams
- , Wouter R. Karthaus
- & Charles L. Sawyers
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Letter |
FOXK1 and FOXK2 regulate aerobic glycolysis
The Forkhead transcription factors FOXK1 and FOXK2, which are induced by starvation, reprogram cellular metabolism to induce aerobic glycolysis.
- Valentina Sukonina
- , Haixia Ma
- & Sven Enerbäck
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Letter |
PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress
Phosphorylation of one of two adjacent serine residues in TSC2 is both required and sufficient for PKG1-mediated cardiac protection against pressure overload in mice; these serine residues provide a genetic tool for the bidirectional regulation of stress-stimulated mTORC1 activity.
- Mark J. Ranek
- , Kristen M. Kokkonen-Simon
- & David A. Kass
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Letter |
Design of amidobenzimidazole STING receptor agonists with systemic activity
A small-molecule agonist for the cGAS–STING pathway has systemic activity in a mouse model of colon cancer.
- Joshi M. Ramanjulu
- , G. Scott Pesiridis
- & John Bertin
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Letter |
A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition
When basal cell carcinoma is treated with a Smoothened inhibitor, a subset of cancer cells evades treatment by switching identity, allowing residual tumours to regrow when treatment is discontinued.
- Brian Biehs
- , Gerrit J. P. Dijkgraaf
- & Frederic J. de Sauvage
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Letter |
Accumulation of succinate controls activation of adipose tissue thermogenesis
A comparative metabolomics approach is used to identify succinate as a key activator of thermogenesis in brown adipose tissue.
- Evanna L. Mills
- , Kerry A. Pierce
- & Edward T. Chouchani
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Letter |
Codon-specific translation reprogramming promotes resistance to targeted therapy
Enzymes that catalyse modifications of wobble uridine 34 tRNA are essential for the survival of melanoma cells that rely on HIF1α-dependent metabolism through codon-dependent regulation of the translation of HIF1A mRNA.
- Francesca Rapino
- , Sylvain Delaunay
- & Pierre Close
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Letter |
Activity-dependent neuroprotective protein recruits HP1 and CHD4 to control lineage-specifying genes
ADNP interacts with the chromatin remodeller CHD4 and the heterochromatin protein HP1 to form a complex termed ChAHP that represses gene expression independently of the histone H3K9me3 modification.
- Veronika Ostapcuk
- , Fabio Mohn
- & Marc Bühler
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Letter |
Mitochondria–lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis
Formation of inter-organelle contacts between mitochondria and lysosomes, regulated by lysosomal RAB7 GTP hydrolysis, allows for bidirectional regulation of mitochondrial and lysosomal dynamics.
- Yvette C. Wong
- , Daniel Ysselstein
- & Dimitri Krainc
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Letter |
Senescence-associated reprogramming promotes cancer stemness
Cellular senescence induced by chemotherapy leads to the acquisition of stemness in cancer cells, which results in enhanced tumour-promoting capacity after forced release or spontaneous escape from the senescent cell-cycle arrest.
- Maja Milanovic
- , Dorothy N. Y. Fan
- & Clemens A. Schmitt
Convergence of coronary artery disease genes onto endothelial cell programs