Reviews & Analysis

Caveolin-1 (CAV1) is best known as a building block of caveolae, flask-shaped ‘little caves’ that buffer the plasma membrane by flattening in response to mechanical stress. CAV1 is now linked to a feature of cellular topography that can respond to mechanical cues and relieve membrane tension: dolines.

In type 2 diabetes, altered lipid metabolism causes a defect in insulin secretion. A study now shows how reduced very long-chain sphingolipids in β cells may impair the export of insulin-processing enzymes from the endoplasmic reticulum. The resulting defect in insulin production causes increased blood glucose concentrations.

IL-2 is a powerful growth factor for T cells. New work shows that immune checkpoint blockade depends upon the presence of IL-2, and that mesenchymal stem cells can be efficiently engineered to safely deliver it directly in advanced tumours to rescue CD8⁺ T cell responsiveness to anti-PD-L1 antibody treatment.

The onset of differentiation has been assumed to follow withdrawal from the cell cycle. A new study shows that keratinocytes initiate differentiation before exiting the cell cycle, allowing the skin to respond rapidly to damage.

Several new technologies have used synthetic RNAs that leverage the cell’s RNA splicing machinery to drive the expression of gene products. A new study now reports a technique to dynamically and non-invasively monitor gene expression by embedding reporters within introns contained in the parent gene.

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.

PTEN, a tumour suppressor, also regulates T cell activation. A new study reports that PTEN acts as a cell-intrinsic rheostat linking TCR- and IL-23-mediated signalling to regulate development of type-17 innate-like T cells in the thymus. This work may have important implications for treating autoimmune and inflammatory diseases.

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.

Kao et al. discuss the metabolic crosstalk between cancer cells and immune cells and how this impacts immune surveillance and anti-tumour immune responses.

Specialized activities of ribosomal components that regulate the expression of specific genes is an emerging field of research. A new study identifies alternative splicing of a ribosomal protein between the peripheral and core regions of glioblastoma tumours to produce isoforms with distinct functions.

Cellular senescence induced by DNA replication and telomere attrition contributes to organ dysfunction, inflammation and impaired immunity. A study reveals that antigen-presenting cells provide telomeric DNA to CD4⁺ T cells in synaptic contact, which enables the suspension of senescence, T cell expansion and long-lived immunity.

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.

Pan and Winkler review key recent advances in the rapidly developing field that focuses on the crosstalk between cancer and the nervous system and how this may be leveraged to inform rational design of cancer therapies.

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.

The mechanisms that underlie cell identity remain poorly understood. A study now dissects the transcriptional trajectories of single cells undergoing malignant transformation or reprogramming to pluripotency and reveals regulators of cell plasticity in these biological processes.

In this Review, Andrew Modzelewski, Johnny Gan Chong, Ting Wang and Lin He discuss how sequences introduced by transposon activities provide raw material for genome innovation and document the distinct evolutionary path of each species.

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.

In this Review, Polyak and colleagues discuss cellular and microenvironmental mechanisms that contribute to intratumour heterogeneity and how this affects immune escape and tumour progression.

Aberrant subcellular localization of proteins contributes to the pathogenesis of cancer. A study now reports that the mis-localization of METTL3, a nuclear N⁶-adenosine methyltransferase, to the cytoplasm promotes gastric cancer by enhancing mRNA translation of a subset of oncogenes, independently of the N⁶-methyladenosine (m⁶A) modification.

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.