Volume 25 Issue 5, May 2023

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.

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.

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.

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.

Acutely damaged lysosomes can regenerate themselves by repurposing damaged membranes. After damage, cytosolic TBC1D15 relocalizes to impaired lysosomes and assembles the autophagic lysosomal reformation machinery to drive this regeneration. This mechanism exemplifies an immediate cellular response to mitigate the crisis of severe lysosomal damage.

The SEL1L–HRD1 endoplasmic reticulum-associated degradation pathway negatively regulates STING-mediated innate immunity by ubiquitinating and targeting STING for proteasomal degradation, thereby limiting its activation.

Carbognin et al. report that ESRRB drives activation of the transcriptional programme regulating the formative transition of naive embryonic stem cells.

Galenza et al. show that basal stem cell progeny seamlessly integrate into a physiologically active barrier epithelium by gestating their future apical surface in a sheltering niche created by a transient occluding junction.

Papsdorf et al. show that mono-unsaturated fatty acids extend lifespan of C. elegans through induction of peroxisomes and lipid droplets in fat tissues and of a lipid signature predictive of decreased lipid oxidation.

Bhattacharya et al. describe a TFEB-independent lysosome membrane regeneration pathway that depends on TBC1D15, which stabilizes autophagic lysosomal reformation proteins, potentiating the formation of lysosomal tubules and dynamin-2-dependent scission.

Sontag et al. show that nuclear misfolded proteins and juxtanuclear cytoplasmic misfolded proteins converge to opposite sides of the nuclear envelope, proximal to nuclear–vacuolar junctions for ESCRT-dependent egress to the vacuole.

Wu et al. show that, upon activation by insulin-like growth factor 1 receptor and AKT, creatine kinase B exhibits a moonlighting function as protein kinase to phosphorylate glutathione peroxidase 4 to prevent its degradation, thereby suppressing ferroptosis and enhancing tumour growth in mice.

Ji et al. report that under basal conditions the SEL1L–HRD1 complex for endoplasmic reticulum-associated degradation ubiquitinates and negatively regulates STING protein levels in the endoplasmic reticulum, hence its activation.

Levra Levron et al. report that epidermal injury elicits the priming of distant memory progenitors that have not contributed in the original healing, but acquire enhanced repair abilities, although favouring field cancerization.

Yan et al. harness genome-wide CRISPR screens and identify ILF3 as a signalling intermediate negatively regulating mTORC1 activation upon amino acid sensing. ILF3 recruits GATOR2 to tether the GATOR complexes to lysosomes and regulate mTORC1 activity.

Yao et al. observe and characterize genomic redistribution of the PBAF complexes upon PBRM1 loss, leading to sustained RELA occupancy by SMARCA4, activation of the NF-kB pathway and enhanced kidney tumourigenesis.

Huang et al. provide a method to generate human gastric stem cell-derived pancreatic islet-like organoids that are capable of restoring glucose homeostasis in diabetic mice.