News & Views

  • News & Views |

    PI3K–Akt signalling downstream of cell-surface receptor activation has long been thought to occur at the plasma membrane. However, surprising evidence now reveals activation of PI3Kα-mediated PI(3,4,5)P3 synthesis on endosomal membranes that is dependent upon the interaction of PI3Kα with the microtubule-associated protein MAP4.

    • Alex G. Batrouni
    •  & Jeremy M. Baskin
  • News & Views |

    There are many challenges in finding an effective, long-lasting and universal cure for the whole cohort of patients with Duchenne muscular dystrophy (DMD). The discovery of H19 lncRNA as a stabiliser of dystrophin may prove to be the missing link to the success of various rescue therapies proposed for treating DMD.

    • Morten Ritso
    •  & Michael A. Rudnicki
  • News & Views |

    Triggering heart repair after myocardial infarction is a challenge in regenerative medicine. A study now shows how ERBB2-mediated YAP activation promotes both cardiomyocyte proliferation and epithelial-to-mesenchymal transition (EMT) in adult mice. EMT initiates cardiomyocyte dedifferentiation and migration and together with proliferation promotes cardiac regeneration.

    • Ainara González-Iglesias
    •  & M. Angela Nieto
  • News & Views |

    Sirtuins are highly conserved enzymes with key roles in life extension in multiple organisms. A study now describes selective autophagic degradation of nuclear SIRT1 in senescent cells. These observations suggest that blocking sirtuin degradation could be a potential approach for anti-ageing therapies.

    • Jay X. Tan
    •  & Toren Finkel
  • News & Views |

    Protein homeostasis preserves stem cell function, but the underlying mechanisms are largely unknown. A study reveals that protein quality control mediated by the endoplasmic reticulum-associated degradation pathway ensures proper expression of MPL, a key cell surface receptor that promotes haematopoietic stem cell function through niche interaction.

    • Kentson Lam
    •  & Robert A. J. Signer
  • News & Views |

    Programmed death ligand-1 (PD-L1) is well known for its role as an immune checkpoint regulator, but little is known about its function in other cellular processes. A study now shows that in tumour cells PD-L1 mediates pyroptosis, an inflammatory form of cell death, by activating the expression of Gasdermine C, ultimately leading to tumour necrosis.

    • María Teresa Blasco
    •  & Roger R. Gomis
  • News & Views |

    Ferroptosis is an iron-dependent mode of cell death driven by lipid peroxidation, capable of explosively propagating through a field of cells. Two studies now explore the mechanisms underlying ferroptotic cell death and its spread, as well as its possible in vivo significance, shedding light on some of the burning questions surrounding ferroptosis.

    • Andrew J. Davidson
    •  & Will Wood
  • News & Views |

    While the formation and concentration of urine are better understood, how kidney epithelial cells generate the energy to drive these functions has remained unclear. A study now reveals that shear stress originating from urinary flow is sensed by the primary cilia of cortical epithelial cells and stimulates lipolysis and oxidative metabolism.

    • Nuria Martinez-Lopez
    •  & Rajat Singh
  • News & Views |

    PD-L1 has been extensively described as the membrane-bound ligand of PD-1. A recent study discovered a previously unknown role for PD-L1, which is able to bind DNA and thus govern different pathways linked to either evasion of immune surveillance or tumour microenvironment inflammation.

    • Alison Jaccard
    •  & Ping-Chih Ho
  • News & Views |

    Studies of stem cell behaviour during regeneration have largely focused on understanding how cells make the choice between self-renewal and differentiation. It remains unclear whether cells undergo smooth transitions during differentiation or pause at selective intermediate states. Three studies now explore this question in lung regeneration.

    • Jamie M. Verheyden
    •  & Xin Sun
  • News & Views |

    Cellular plasticity allows tumours to adapt to and overcome therapeutic challenges. A recent study uncovered the gene regulatory networks that govern cell states and phenotype switching in melanoma, opening up possibilities to therapeutically target cell states or phenotypic plasticity to render melanoma cells more vulnerable to treatment.

    • Nicole M. Aiello-Couzo
    •  & Yibin Kang
  • News & Views |

    In this issue of Nature Cell Biology, Mercier et al. show that acute changes in membrane tension may be a physiological trigger for ESCRT assembly, which drives membrane scission, luminal vesicle budding, and a wide array of other membrane remodelling events throughout the cell.

    • Robert C. Piper
  • News & Views |

    There is increasing appreciation that many proteins self-aggregate in cells to form functional subcompartments, some of which exist as a separate liquid phase. A study now identifies the biophysical properties of AKAP95 protein condensates as critical for supporting cancer cell proliferation and RNA splicing.

    • Bo Liu
    •  & Omar Abdel-Wahab
  • News & Views |

    Secretory proteins undergo multiple rounds of co- and post-translational quality control checks inside the cell, but how their integrity is maintained outside the cell is an emerging topic. A study establishes a model system to investigate how the extracellular proteome is protected and integrates its findings into existing immune pathways.

    • Brant M. Webster
    • , Holly K. Gildea
    •  & Andrew Dillin
  • News & Views |

    Cellular senescence has been widely recognised for decades as a stable arrest of cell proliferation. A recent study identifies senescence establishment and maintenance as a dynamic and reversible process regulated by (in)activation of a predetermined enhancer landscape controlled by the pioneer transcription factor AP-1.

    • Sara Zumerle
    •  & Andrea Alimonti
  • News & Views |

    Stem cells tightly link their metabolism to cell fate decisions; however, how cancers co-opt and bypass metabolic pathways for growth advantage remains unclear. New evidence in this issue highlights how cancer stem cells avoid epigenetically driven differentiation by shutting down endogenous serine synthesis and becoming serine auxotrophs.

    • Daniel Haensel
    •  & Anthony E. Oro
  • News & Views |

    The transcription factor oestrogen receptor alpha (ERα) has long been targeted for therapeutic benefit in cancer, but drug resistance can emerge through a multitude of mechanisms. A study now reveals how the ERα cistrome can become reprogrammed to confer resistance to tamoxifen in breast cancer.

    • Xiaoli S. Wu
    •  & Christopher R. Vakoc
  • News & Views |

    CRISPR base editors can induce single-base-pair changes in the genome, although they are often inefficient. A study now shows that fusion of the DNA-binding domain of RAD51 to base editors enhances both the efficiency and the targeting range of optimized enzymes. These ‘hyper-editors’ offer effective tools for disease modeling and gene therapy.

    • Alyna Katti
    •  & Lukas E. Dow
  • News & Views |

    Pluripotent cells generate all types of cells in the body and have largely been classified dichotomously into two types: naïve and primed. Arguing against a binary classification system, a study now discovers a unique transition state between naïve and primed pluripotency and describes the signals that control this transition.

    • Carolyn E. Dundes
    •  & Kyle M. Loh
  • News & Views |

    Active transport along microtubules by molecular motors is a crucial cellular process that is disrupted in human diseases. Single-molecule studies from three independent groups reveal a new molecular mechanism for how cells control the activity of the complex microtubule motor cytoplasmic dynein via the neurodevelopmental protein LIS1.

    • Richard J. McKenney
  • News & Views |

    Post-translational histone modifications are important regulators of nuclear reprogramming. A study now reveals that histone lysine demethylase KDM4A-mediated H3K9me3 demethylation in mammalian oocytes is essential for zygotic genome activation and preimplantation development.

    • Julie Brind’Amour
    •  & Matthew C. Lorincz
  • News & Views |

    YAP and TAZ, paralogous mammalian genes, act as the key transcriptional effectors of the Hippo pathway. Two recent reports show that both YAP and TAZ form liquid–liquid phase-separated bodies that promote gene transcription by engaging in super-enhancers.

    • J. Matthew Franklin
    •  & Kun-Liang Guan
  • News & Views |

    Piwi proteins are aberrantly induced in human tumours, but their function in cancer has been poorly understood. A study now shows that in the absence of piRNA loading, human PIWIL1 promotes pancreatic cancer metastasis by acting as a co-activator of the anaphase-promoting complex/cyclosome (APC/C) to degrade the cell-adhesion protein Pinin.

    • Fan Yao
    •  & Li Ma
  • News & Views |

    The lack of endogenous reporter lines is a bottleneck in the study of subcellular dynamics in human adult stem cell (ASC)-derived organoids. An approach using CRISPR–Cas9-mediated homology-independent organoid transgenesis (CRISPR–HOT) in ASC-derived organoids now narrows the gap between basic research and translational studies in human organoids.

    • Qiutan Yang
    • , Koen C. Oost
    •  & Prisca Liberali
  • News & Views |

    Misfolded proteins in the endoplasmic reticulum (ER) are returned to the cytosol and destroyed by a process known as ER-associated degradation (ERAD). Hrd1 has been implicated as the channel that mediates the transport of ERAD substrates to the cytosol. A study demonstrates that Hrd1 is gated by autoubiquitination and a soluble ERAD substrate.

    • Miguel Betegon
    •  & Jeffrey L. Brodsky
  • News & Views |

    Gene editing holds promise for the treatment of cancers that are driven by well-characterised molecular alterations. A study now provides a proof of concept for the feasibility of in vivo gene editing to correct TERT mutations in glioblastoma, providing a platform for the direct manipulation of genetic alterations to reduce tumour growth.

    • Katie Troike
    •  & Justin D. Lathia
  • News & Views |

    Understanding the metabolic rewiring of pancreatic ductal adenocarcinoma is an emerging strategy for identifying cancer-associated liabilities and improving treatment. A new study now elucidates the function of the transaminase BCAT2 in the early stages of tumor development, providing insights that could stimulate novel therapeutic strategies.

    • Mattia Falcone
    •  & Oliver D. K. Maddocks
  • News & Views |

    The ribosome decodes messenger RNAs and constructs proteins based on the genetic blueprint. Ribosomes also associate with non-coding RNAs, such as PIWI-interacting RNA (piRNA) precursors, during the meiotic pachytene stage. Intriguingly, the ribosome mediates pachytene piRNA biogenesis by guiding endonucleolytic cleavage of piRNA precursors.

    • Yuanhui Mao
    •  & Shu-Bing Qian
  • News & Views |

    A mechanism of secretory autophagy explains aspects of the packaging of proteins and RNA into extracellular vesicles and paves the way to a better understanding of their biological roles and medical applications.

    • Janusz Rak
  • News & Views |

    The molecular clock regulates the rhythmic transcription of myriad genes, leading to a circadian pattern of expression of the encoded proteins. A study demonstrates circadian regulation of expression of components of the protein secretory pathway, providing a mechanism to generate circadian patterns of secreted protein expression.

    • Thomas P. Burris
  • News & Views |

    Different types of stromal cells in the bone marrow associate to form niches that support differentiating blood cells and ensure lifelong production of all major blood lineages. A study now combines single-cell and spatial transcriptomics with imaging to infer the cellular composition and spatial architecture of specific niches.

    • Daniel Lucas
    • , Nathan Salomonis
    •  & H. Leighton Grimes
  • News & Views |

    Tangential expansion of neural stem cells in the mammalian neocortex increases the number of cortical columns. A new study shows that neural stem cells that become detached from the apical surface during division regenerate an apical endfoot to ensure tangential expansion in the early stage but later lose this ability when radial expansion occurs.

    • Masafumi Tsuboi
    •  & Yukiko Gotoh
  • News & Views |

    Tendons have limited regenerative potential, and injuries often cause scarring. A study now identifies a tendon stem cell population that contributes to regeneration and a tendon fibro–adipogenic progenitor population involved in fibrosis.

    • Ashley L. Titan
    •  & Michael T. Longaker
  • News & Views |

    In mammals, a circadian timing system composed of a master clock in the brain’s suprachiasmatic nucleus and oscillators in peripheral organs drives daily rhythms of behavior and physiology. A study now reveals that the periodic oxidation of the CLOCK protein enhances the amplitude of cyclic gene expression and affects the daily rhythms of behavior.

    • Ueli Schibler
  • News & Views |

    Pancreatic ductal adenocarcinoma displays high levels of cellular heterogeneity, which is associated with drug resistance and high metastatic rates. A new study shows that tetraspanin CD9 marks PDAC tumour-initiating cells and functions as a regulator of glutamine metabolism.

    • Xiphias Ge Zhu
    •  & Kivanc Birsoy
  • News & Views |

    After mitosis chromosomes are drastically reshaped. A study now charts the dynamics of this conformational change at high temporal resolution. During the shift from one loop-forming complex (condensin) to another (cohesin), an intermediate chromosome folding state exists in which neither of these complexes are associated with chromatin.

    • Ning Qing Liu
    •  & Elzo de Wit
  • News & Views |

    PTEN is a phosphatase that functions as a tumour suppressor by antagonizing the PI3K–AKT pathway. However, a study now demonstrates that translational variants of PTEN enable new interactions between PTEN and the COMPASS complex, identifying a new role for PTEN in modifying gene expression via COMPASS-mediated histone H3 lysine 4 methylation.

    • Justin Taylor
    •  & Omar Abdel-Wahab
  • News & Views |

    The non-specific lethal (NSL) complex is a highly conserved MOF acetyltransferase-containing complex. A recent study now shows that the NSL complex acetylates a new non-histone target, Lamin A/C and reveals the NSL complex as a crucial factor in maintaining nuclear architecture and genome integrity.

    • Varvara V. Popova
    •  & Jerry L. Workman
  • News & Views |

    Endosomes are central stations for converging proteins from biosynthetic pathways and endocytic routes. Many endosomal proteins are sorted to the plasma membrane or the Golgi despite the lysosome being the primary endosomal fate. SNX5 and SNX6 are now revealed to decode a conserved bipartite signal to mediate protein sorting to the Golgi or the plasma membrane.

    • Wanjin Hong
  • News & Views |

    Cell identity is shaped by a complex interplay between transcription factors, enhancers and genome organisation. A study now reveals a dynamic role for the transcription factor KLF4 in directing gene regulatory interactions during pluripotent cell reprogramming, demonstrating that transcription factors can function as chromatin organisers.

    • Peter J. Rugg-Gunn
  • News & Views |

    Assembly of the mitotic spindle requires timely separation of the centrosomes. Their movement apart is driven by the plus-end-directed kinesin Eg5. A new study demonstrates that the kinesin KIFC3 provides an opposing microtubule-based cohesive force that modulates centrosome separation and ensures accurate chromosome segregation.

    • Ciaran G. Morrison
  • News & Views |

    Tumours elicit an immune attack that can stifle their growth, but they can also recruit inflammatory immune cells that suppress this response. A new study identifies distinct immune subtypes of triple-negative breast cancer with two different inflammatory cell types: macrophages or neutrophils. The immune subtype dictates the response to immunotherapy.

    • Laura Maiorino
    •  & Mikala Egeblad
  • News & Views |

    Activation of the receptor EGFR (ERBB1) occurs in response to viral infections and regulates antiviral immunity. A new study now shows that the receptor HER2 (ERBB2) negatively regulates STING signaling in response to DNA viruses and expands the model and mechanisms by which surface-receptor tyrosine kinases perform important intracellular regulatory functions.

    • Ian D. Odell
    •  & Richard A. Flavell
  • News & Views |

    Migrasomes are a recently discovered type of extracellular vesicles that are characteristically generated along retraction fibers in migrating cells. Two studies now show how migrasomes are formed and how they function in the physiologically relevant context of the developing zebrafish embryo.

    • Stefania Tavano
    •  & Carl-Philipp Heisenberg
  • News & Views |

    Loss-of-function mutations in the ubiquitin ligase Parkin are a cause of Parkinson’s disease. Parkin also has tumour-suppressor activity, although how Parkin prevents cancer is unclear. Unexpectedly, Parkin is found to suppress cancer by inhibiting an inflammatory type of cell death called necroptosis.

    • Kai Cao
    •  & Stephen W. G. Tait
  • News & Views |

    Tissue renewal requires proliferative progenitors with long-lasting potential. Designated stem cells within specialized niches are considered to be the primary mechanism for this requirement. Recent studies show that dispersed equipotent progenitors are sufficient to account for fast-paced cellular dynamics in skin oil glands and foetal gut epithelium.

    • Qing Nie
    •  & Maksim V. Plikus
  • News & Views |

    The ability of cancer cells to adapt to external and internal stresses is critical for tumourigenesis. A new study now shows that the integrated stress response is critical for tumour cell adaptation to stress induced by c-MYC activation, providing mechanistic insights into tumour responses to intrinsic stresses with implications for cancer therapies.

    • Kirk A. Staschke
    •  & Ronald C. Wek
  • News & Views |

    Different subclones cooperate to support tumour heterogeneity and growth, but the effect on metastasis is unclear. A new study now shows that, as non-cell-autonomous drivers, minor cancer cell subclones instigate growth at distant sites of otherwise non-metastatic cancer cells. This is mediated systemically by perturbation in the metastatic tissue.

    • Luigi Ombrato
    •  & Ilaria Malanchi
  • News & Views |

    Tumour-secreted microvesicles carry bioactive molecules that can be transferred to recipient cells, impacting tumour progression. A study now shows that ARF6 drives miRNA loading into tumour microvesicles through interaction with pre-miRNA–Exportin-5 complexes, thus shedding light on specific cargo packaging mechanisms.

    • Gonçalo Rodrigues
    • , Haiying Zhang
    •  & David Lyden
  • News & Views |

    Centromere identity must be maintained through multiple generations. A new study reveals a Constitutive Centromere-Associated Network (CCAN)-dependent retention of CENP-A, a key epigenetic mark for centromeres, in centromeres during DNA replication and a replication-dependent error correction to eliminate ectopic CENP-A in chromosome arms.

    • Masatoshi Hara
    •  & Tatsuo Fukagawa