Reviews & Analysis

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.

The cGAS–STING cytosolic double-stranded-DNA-sensing pathway provides protection against infection but also contributes to inflammatory pathology and thus must be tightly regulated. In this issue, Jie et al. find that endoplasmic-reticulum-associated degradation of the adaptor STING by SEL1L–HRD1 controls steady-state STING levels to limit STING-driven inflammation.

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.

Direct conversions offer an alternative approach to generate insulin-producing cells for cell therapy in diabetes. A study reports a method to convert human stomach-derived gastric stem cells into functional insulin-producing cells through a unique differentiation path.

Skin wounds induce an epigenetic memory that accelerates the healing of subsequent injuries. The underlying mechanism is now shown to involve epigenetic chromatin modifications in stem cells from a field of distal hair follicles that surround the injury. Importantly, this mechanism also results in a predisposition for skin cancer development.

Coordination of protein quality control processes across organelles is poorly understood. A study now shows that the cytosolic juxtanuclear quality control (JUNQ) and intranuclear quality control (INQ) compartments face each other on opposite sides of the nuclear envelope before their vacuolar degradation, promoting proteostasis.

The house-keeping aminoacyl-tRNA synthetases are increasingly recognized for their regulatory roles beyond protein synthesis. Research now uncovers a function of nuclear arginyl-tRNA synthetase in the regulation of alternative mRNA splicing through SRRM2 in response to inflammation and decreased arginine levels.

In adult Drosophila, the sense of touch is mediated by mechanosensory organs, namely tactile bristles in the epidermis. A new study reveals that a previously unknown type of epidermal cell, named the F-cell, is recruited to ensheath the tactile bristle and is required for touch sensing.

DNMT3A is best known for its de novo DNA methyltransferase activity. But a new study shows that the protein also has a role in RNA splicing during activation of embryonic and haematopoietic stem cells. This introduces a new perspective for approaching diseases associated with DNMT3A mutations.

Programmed cell death (PCD) enables cells to co-ordinate their exit to benefit the surviving organism. A new study describes how cells can programme their death by inducing extensive disulfide bonding of the actin cytoskeleton in response to an imbalance of cystine, a raw material for glutathione production.

Activation of a crucial immune adaptor protein, STING, is tightly regulated by subcellular trafficking, but how it is deactivated remains less well defined. A study now shows that ESCRT-dependent encapsulation of STING-carrying vesicles by lysosomal compartments — through the process of microautophagy — mediates the termination of STING signalling.

A study using a multi-organoid platform and state-of-the-art transcriptional profiling identifies potential therapeutic targets against SARS-CoV-2. The authors find that CIART, a gene involved in circadian regulation, promotes SARS-CoV-2 infection by regulating the retinoid X receptor pathway and fatty acid synthesis.

Extracellular matrix (ECM) stiffening is a hallmark of cancer aggressiveness. Diverse ECM environments can alter the number and cargo of small extracellular vesicles (sEVs). Wu et al. now delineate a pathway from ECM stiffness to FAK/PI3K/Akt signalling and Rab8-induced sEV secretion, promoting cancer growth.

An ependymoma subtype is driven by fusion proteins related to the transcriptional regulator YAP1. Research now shows that localization of these fusion proteins within nuclear condensates is necessary and sufficient for tumour formation through the activation of various genetic and epigenetic oncogenic mechanisms.

Extramitochondrial coenzyme Q (CoQ) can function as a potent anti-ferroptosis radical trapper. However, it is largely unknown how CoQ is transported from mitochondria to the plasma membrane. A study now suggests that PARL-mediated STARD7 processing is responsible for the cellular distribution of CoQ.

Tight regulation of the activity of EWS–ETS fusion proteins is essential for the growth of Ewing sarcomas. Two new studies show that the transcriptional repressor ETV6 is essential for tumour growth, acting to restrain fusion-protein-mediated gene activation, and revealing the importance of tissue-specific transcription factors to oncogenesis.

End-binding proteins attach to the dynamic plus-ends of microtubules in order to regulate microtubule polymerization and the transport of other plus-end tracking proteins (+TIPs). Three new studies dissect the multivalent interactions that constitute distinct +TIP networks and reveal that they give rise to liquid-like biomolecular condensates.

The bone marrow is the daily production site for hundreds of billions of blood cells. A new study adds evidence that, during ageing, signals emanating from bone-marrow stromal cells shift to produce inflammatory factors that skew blood-cell output, driving age-related tissue deterioration.

Tumour-initiating cells are resistant to challenging growth conditions during the initiation of pancreatic cancer, but how transformed cells acquire a stress-resistant, tumour-initiating state remains unclear. Here, the authors identify a signalling cascade in which LPAR4 induces fibronectin production, cancer stemness and a tumour-initiating niche.

Bivalent genes are regulated by a balance between repressive Polycomb group proteins and activating trithorax group proteins. A new study has revealed that MENIN, an accessory component of KMT2A/B methyltransferase complexes, has an unorthodox role in repressing bivalent genes, alongside Polycomb repressive complexes.