Nature Cell Biology
Nature Cell Biology publishes peer-reviewed original research of the highest quality in all areas of cell biology with an emphasis on studies that provide insights into the molecular mechanisms underlying cellular processes. The journal’s scope is broad and ranges from cytoskeletal dynamics, membrane transport, adhesion and migration, cell division, signalling pathways, development and stem cells, to molecular and cellular mechanisms underlying cancer. Nature Cell Biology provides timely and informative coverage of cell biological advances.
Mitochondria are multifaceted organelles with crucial roles in energy generation, cellular signalling and a range of synthesis pathways. The study of mitochondrial biology is complicated by its own small genome, which is matrilineally inherited and not subject to recombination, and present in multiple, possibly different, copies. Recent methodological developments have enabled the analysis of mitochondrial DNA (mtDNA) in large-scale cohorts and highlight the far-reaching impact of mitochondrial genetic variation. Genome-editing techniques have been adapted to target mtDNA, further propelling the functional analysis of mitochondrial genes. Mitochondria are finely tuned signalling hubs, a concept that has been expanded by advances in methodologies for studying the function of mitochondrial proteins and protein complexes. Mitochondrial respiratory complexes are of dual genetic origin, requiring close coordination between mitochondrial and nuclear gene-expression systems (transcription and translation) for proper assembly and function, and recent findings highlight the importance of the mitochondria in this bidirectional signalling. Auwerx and colleagues review recent advances in mitochondrial genetics, proteomics and biochemistry that emphasize the far-reaching impact of mitochondrial genetic variation and the role of mitochondria as finely tuned signalling hubs.
Tissue deformations are a central feature of development, from early embryogenesis, growth and building the body plan to the establishment of functional organs. These deformations often result from active contractile forces generated by cells and cell collectives, and are mediated by changes in their mechanical properties. Mechanical forces drive the formation of functional organ architectures, but they also coordinate cell behaviour and fate transitions, ensuring robustness of development. Advances in microscopy, genetics and chemistry have enabled increasingly powerful tools for measuring, generating and perturbing mechanical forces. Here we discuss approaches to measure and manipulate mechanical forces with a focus on developmental processes, ranging from quantification of molecular interactions to mapping the mechanical properties of tissues. We focus on contemporary methods, and discuss the biological discoveries that these approaches have enabled. We conclude with an outlook to methodologies at the interface of physics, chemistry and biology to build an integrated understanding of tissue morphodynamics. This Review discusses the recent advances in experimental approaches to interrogate the mechanical forces that mediate tissue deformations during development, highlighting the insights afforded at both the cellular and tissue scales.
The existence of an endoplasmic reticulum (ER)–Golgi intermediate compartment (ERGIC) in plant cells has long been debated. In our study we identified a dynamic Golgi-independent tubular network that transports ER-derived cargos and interacts with pre-existing Golgi to mature into new pre-Golgi cisternae in a lipid-dependent manner.
Cell surface acidification has key roles in both cell migration and bone resorption. A study now identifies a pathway whereby growth factor signalling induces local acidification, driving sialic acid removal and galectin-3-mediated integrin internalization.
The activation of ferroptosis has shown great potential for cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into S-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of glutathione peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving cancer therapy efficacy, by acting to reduce the counteraction of ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability. Fan et al. report a role for PRMT5 in regulating GPX4 stability and ferroptosis sensitivity through arginine methylation, which may be targeted to inhibit tumour development.
Highly aggressive tumours have evolved to restrain the cGAS–STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ. Phosphorylated ADSL interacts with STING at the endoplasmic reticulum, where ADSL-produced fumarate binds to STING, leading to the inhibition of cGAMP binding to STING, STING activation and subsequent IRF3-dependent cytokine gene expression. Disrupting the ADSL–STING association promotes STING activation and blunts tumour growth. Notably, a combination treatment with ADSL endoplasmic reticulum translocation-blocking peptide and anti-PD-1 antibody induces an additive inhibitory effect on tumour growth accompanying a substantially increased immune response. Notably, ADSL T350 phosphorylation levels are inversely correlated with levels of STING activation and predicate poor prognosis in patients with breast cancer. These findings highlight a pivotal role of the metabolite fumarate in inhibiting STING activation and uncover new strategies to improve immune-checkpoint therapy by targeting ADSL-moonlighting function-mediated STING inhibition. Duan, Hu, Han, Lei, Wang et al. report that ADSL-mediated production of fumarate suppresses STING activation and impairs T cell and NK cell infiltration, thereby facilitating immune evasion in breast cancer.
Understanding how cells respond differently to perturbation is crucial in cell biology, but existing methods often fail to accurately quantify and interpret heterogeneous single-cell responses. Here we introduce the perturbation-response score (PS), a method to quantify diverse perturbation responses at a single-cell level. Applied to single-cell perturbation datasets such as Perturb-seq, PS outperforms existing methods in quantifying partial gene perturbations. PS further enables single-cell dosage analysis without needing to titrate perturbations, and identifies ‘buffered’ and ‘sensitive’ response patterns of essential genes, depending on whether their moderate perturbations lead to strong downstream effects. PS reveals differential cellular responses on perturbing key genes in contexts such as T cell stimulation, latent HIV-1 expression and pancreatic differentiation. Notably, we identified a previously unknown role for the coiled-coil domain containing 6 (CCDC6) in regulating liver and pancreatic cell fate decisions. PS provides a powerful method for dose-to-function analysis, offering deeper insights from single-cell perturbation data. In two independent studies, Song et al. and Jiang, Dalgarno et al. present computational frameworks, perturbation-response score and Mixscale, respectively, to determine individual cellular variation in response to perturbation.
Recent advancements in functional genomics have provided an unprecedented ability to measure diverse molecular modalities, but predicting causal regulatory relationships from observational data remains challenging. Here, we leverage pooled genetic screens and single-cell sequencing (Perturb-seq) to systematically identify the targets of signalling regulators in diverse biological contexts. We demonstrate how Perturb-seq is compatible with recent and commercially available advances in combinatorial indexing and next-generation sequencing, and perform more than 1,500 perturbations split across six cell lines and five biological signalling contexts. We introduce an improved computational framework (Mixscale) to address cellular variation in perturbation efficiency, alongside optimized statistical methods to learn differentially expressed gene lists and conserved molecular signatures. Finally, we demonstrate how our Perturb-seq derived gene lists can be used to precisely infer changes in signalling pathway activation for in vivo and in situ samples. Our work enhances our understanding of signalling regulators and their targets, and lays a computational framework towards the data-driven inference of an ‘atlas’ of perturbation signatures. In two independent studies, Song et al. and Jiang, Dalgarno et al. present computational frameworks, perturbation-response score and Mixscale, respectively, to determine individual cellular variation in response to perturbation.
Nature Cell Biology - Publisher Correction: Growth factor-triggered de-sialylation controls glycolipid-lectin-driven endocytosis
Endoplasmic reticulum (ER)-to-Golgi trafficking is a central process of the secretory system of eukaryotic cells that ensures proper spatiotemporal sorting of proteins and lipids. However, the nature of the ER–Golgi intermediate compartments (ERGICs) and the molecular mechanisms mediating the transition between ERGICs and the Golgi, as well as the universality of these processes among eukaryotes, remain undiscovered. Here we identify a reticulated tubulo-vesicular network, labelled by MEMBRIN proteins, that is mostly independent of the Golgi, highly dynamic at the ER–Golgi interface and crossed by ER-induced released luminal cargos. We find that plant ERGICs become stabilized by the interaction they establish with pre-existing Golgi and gradually mature into Golgi cisternae, this process being dependent on C24-ceramide sphingolipids. Our study is a major twist in the understanding of the Golgi, as it identifies that the ERGICs in plants comprise a Golgi-independent and highly dynamic tubular network from which arise more stable Golgi-associated pre-cisternae structures. Fougère, Grison et al. show that the ER–Golgi intermediate compartment (ERGIC) in plants is a tubulo-vesicular network marked by MEMBRIN proteins that is largely Golgi-independent. The plant ERGIC matures into Golgi cisternae, in a process that depends on sphingolipids.
Recent discoveries in the field of large extracellular vesicles have revealed a greater diversity in subtypes than was appreciated even only a decade or so ago. A study now describes a cell-autonomous, motile, organelle-rich extracellular vesicle with cell-like functions and the largest one yet — the blebbisome.
Glycolipid-lectin-driven endocytosis controls the formation of clathrin-independent carriers and the internalization of various cargos such as β1 integrin. Whether this process is regulated in a dynamic manner remained unexplored. Here we demonstrate that, within minutes, the epidermal growth factor triggers the galectin-driven endocytosis of cell-surface glycoproteins, such as integrins, that are key regulators of cell adhesion and migration. The onset of this process—mediated by the Na+/H+ antiporter NHE1 as well as the neuraminidases Neu1 and Neu3—requires the pH-triggered enzymatic removal of sialic acids whose presence otherwise prevents galectin binding. De-sialylated glycoproteins are then retrogradely transported to the Golgi apparatus where their glycan make-up is reset to regulate EGF-dependent invasive-cell migration. Further evidence is provided for a role of neuraminidases and galectin-3 in acidification-dependent bone resorption. Glycosylation at the cell surface thereby emerges as a dynamic and reversible regulatory post-translational modification that controls a highly adaptable trafficking pathway. MacDonald et al. show that EGF triggers de-sialylation of plasma membrane glycoproteins like integrins in a mechanism that depends on the Na+/H+ antiporter NHE1 and the neuraminidases Neu1 and Neu3. Integrins are trafficked to the Golgi and re-sialylated.
Cells secrete a large variety of extracellular vesicles (EVs) to engage in cell-to-cell and cell-to-environment intercellular communication. EVs are functionally involved in many physiological and pathological processes by interacting with cells that facilitate transfer of proteins, lipids and genetic information. However, our knowledge of EVs is incomplete. Here we show that cells actively release exceptionally large (up to 20 µm) membrane-enclosed vesicles that exhibit active blebbing behavior, and we, therefore, have termed them blebbisomes. Blebbisomes contain an array of cellular organelles that include functional mitochondria and multivesicular endosomes, yet lack a definable nucleus. We show that blebbisomes can both secrete and internalize exosomes and microvesicles. Blebbisomes are released from normal and cancer cells, can be observed by direct imaging of cancer cells in vivo and are present in normal bone marrow. We demonstrate that cancer-derived blebbisomes contain a plethora of inhibitory immune checkpoint proteins, including PD-L1, PD-L2, B7-H3, VISTA, PVR and HLA-E. These data identify a very large, organelle-containing functional EV that act as cell-autonomous mobile communication centres capable of integrating and responding to signals in the extracellular environment. Jeppesen, Sanchez et al. identify blebbisomes as large membrane-enclosed vesicles containing organelles and secreted by cells. Blebbisomes can both secrete and internalize exosomes and microvesicles.
Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H2O2, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H2O2-rich microenvironments (H2O2 hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H2O2 underwent partial epithelial–mesenchymal transition through p38–MYC axis activation and migrated away from H2O2 hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H2O2 hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation. Ueda et al. develop a sensor targeted to tumour cells that tracks extracellular H2O2. Tumour cells in H2O2 hotspots undergo partial epithelial–mesenchymal transition and migrate away from H2O2 hotspots. This is not seen in NRF2-hyperactivated tumours.
Recent machine-learning (ML)-based advances in single-cell data science have enabled the stratification of human tissue donors at single-cell resolution, promising to provide valuable diagnostic and prognostic insights. However, such insights are susceptible to biases. Here we discuss various biases that emerge along the pipeline of ML-based single-cell analysis, ranging from societal biases affecting whose samples are collected, to clinical and cohort biases that influence the generalizability of single-cell datasets, biases stemming from single-cell sequencing, ML biases specific to (weakly supervised or unsupervised) ML models trained on human single-cell samples and biases during the interpretation of results from ML models. We end by providing methods for single-cell data scientists to assess and mitigate biases, and call for efforts to address the root causes of biases. This Perspective discusses the various biases that can emerge along the pipeline of machine learning-based single-cell analysis and presents methods to train models on human single-cell data in order to assess and mitigate these biases.
Tissue patterning coordinates morphogenesis, cell dynamics and fate specification. Understanding how precision in patterning is robustly achieved despite inherent developmental variability during mammalian embryogenesis remains a challenge. Here, based on cell dynamics quantification and simulation, we show how salt-and-pepper epiblast and primitive endoderm (PrE) cells pattern the inner cell mass of mouse blastocysts. Coupling cell fate and dynamics, PrE cells form apical polarity-dependent actin protrusions required for RAC1-dependent migration towards the surface of the fluid cavity, where PrE cells are trapped due to decreased tension. Concomitantly, PrE cells deposit an extracellular matrix gradient, presumably breaking the tissue-level symmetry and collectively guiding their own migration. Tissue size perturbations of mouse embryos and their comparison with monkey and human blastocysts further demonstrate that the fixed proportion of PrE/epiblast cells is optimal with respect to embryo size and tissue geometry and, despite variability, ensures patterning robustness during early mammalian development. Moghe et al. show that mouse embryonic primitive endoderm cells migrate towards the inner cell mass-cavity interface, depositing an extracellular matrix gradient that may guide migration. Primitive endoderm to epiblast ratios may enable robust patterning across embryos and sizes.
Nature Cell Biology - Author Correction: Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing
Nature Cell Biology - Enhancers activate from afar
Nature Cell Biology - Mesoderm FN1 shaping the heart
Nature Cell Biology - Restoring placental methylome
The selective destruction of ribosomal subunits through autophagy (‘ribophagy’) is crucial for maintaining cellular protein homeostasis under stress. Findings from various model systems highlight the conserved function of the Rpl12 protein in ribophagy, and show its importance in cellular health and the response to environmental stresses.
Ribophagy is a selective autophagic process that regulates ribosome turnover. Although NUFIP1 has been identified as a mammalian receptor for ribophagy, its homologues do not exist in yeast and nematodes. Here we demonstrate that Rpl12, a ribosomal large subunit protein, functions as a conserved ribophagy receptor in multiple organisms. Disruption of Rpl12–Atg8s binding leads to significant accumulation of ribosomal proteins and rRNA, while Atg1-mediated Rpl12 phosphorylation enhances its association with Atg11, thus triggering ribophagy during starvation. Ribophagy deficiency accelerates cell death induced by starvation and pathogen infection, leading to impaired growth and development and a shortened lifespan in both Caenorhabditis elegans and Drosophila melanogaster. Moreover, ribophagy deficiency results in motor impairments associated with ageing, while the overexpression of RPL12 significantly improves movement defects induced by starvation, ageing and Aβ accumulation in fly models. Our findings suggest that Rpl12 functions as a conserved ribophagy receptor vital for ribosome metabolism and cellular homeostasis. Chen, Hu, Zhao, Fang and colleagues show that the ribosomal large subunit protein Rpl12 functions as a conserved ribophagy receptor in multiple organisms.
Layered control of oncogenic protein dosage enables the hallmarks of cancer, but specific regulators of oncogene mRNA translation remain unknown. A study now reports RMB42 as a regulator of the MYC by remodelling its RNA structure and increasing translation efficiency, highlighting a potential therapeutic avenue to target MYC-driven cancers.
Autophagic mechanisms that maintain nuclear envelope homoeostasis are bulwarks to ageing and disease. Here we define a quantitative and ultrastructural timeline of nuclear macroautophagy (nucleophagy) in yeast by leveraging four-dimensional lattice light sheet microscopy and correlative light and electron tomography. Nucleophagy begins with a rapid accumulation of the selective autophagy receptor Atg39 at the nuclear envelope and finishes in ~300 s with Atg39-cargo delivery to the vacuole. Although there are several routes to the vacuole, at least one pathway incorporates two consecutive membrane fission steps: inner nuclear membrane (INM) fission to generate an INM-derived vesicle in the perinuclear space and outer nuclear membrane fission to liberate a double-membraned vesicle to the cytosol. Outer nuclear membrane fission occurs independently of phagophore engagement and instead relies surprisingly on dynamin-like protein 1 (Dnm1), which is recruited to sites of Atg39 accumulation by Atg11. Loss of Dnm1 compromises nucleophagic flux by stalling nucleophagy after INM fission. Our findings reveal how nuclear and INM cargo are removed from an intact nucleus without compromising its integrity, achieved in part by a non-canonical role for Dnm1 in nuclear envelope remodelling. Mannino et al. provide a quantitative and ultrastructural timeline of nucleophagy in yeast with lattice light sheet microscopy and correlative light and electron tomography. They identify a role for dynamin-like protein 1 in outer nuclear membrane fission.
It is an exciting time for lipid metabolism and membrane cell biologists as technological progress has increased our ability to study lipids in cells. We asked leaders studying lipid cell biology from different perspectives to share what questions they are most interested in and what tools they believe the field is currently lacking.
Oncogenic protein dosage is tightly regulated to enable cancer formation but how this is regulated by translational control remains unknown. The Myc oncogene is a paradigm of an exquisitely regulated oncogene and a driver of pancreatic ductal adenocarcinoma (PDAC). Here we use a CRISPR interference screen in PDAC cells to identify activators of selective MYC translation. The top hit, the RNA-binding protein RBM42, is highly expressed in PDAC and predicts poor survival. We show that RBM42 binds and selectively regulates the translation of MYC and a precise suite of pro-oncogenic transcripts, including JUN and EGFR. Mechanistically, we find that RBM42 binds and remodels the MYC 5′ untranslated region structure, facilitating the formation of the translation pre-initiation complex. Importantly, RBM42 is necessary for PDAC tumorigenesis in a Myc-dependent manner in vivo. This work transforms the understanding of the translational code in cancer and illuminates therapeutic openings to target the expression of oncogenes. Kovalski et al. perform a genome-wide CRISPRi screen for selective MYC mRNA translation regulators and identify RBM42 as a ribosome-associated protein that modulates translation of MYC and an oncogenic mRNA programme required for pancreatic cancer growth.
Accurate protein targeting is a crucial aspect of many biological pathways such as ribosome assembly. Most eukaryotes require two sets of ribosomes assembled in the nucleus and mitochondria. A new study reveals how a cytoplasmic ribosomal protein uS5 evolved a unique signal to avoid being mistargeted to the mitochondria.
In each cell division during early embryogenesis, daughter cells acquire half the size of the mother cell. A study now reports that cytoplasmic flows sensing the cell boundaries allow daughter cells to adapt to their new size and reform their nuclear envelope in the right position.
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