Research Briefing

During early mouse development, a fluid-filled lumen inflates the embryo. Membrane protrusions called inverse blebs have been found to form at cell–cell contacts. Cycles of inverse bleb filling and unloading act as hydraulic pumps and contribute to the formation of the lumen.

Using single-cell RNA sequencing analysis of bone-colonizing tumour cells and in vivo screening, lymphotoxin-β (LTβ) was identified as a key factor promoting bone colonization and outgrowth of breast cancer metastases. Blocking LTβ signalling significantly suppressed bone metastasis, highlighting its potential as a therapeutic target for breast cancer with bone metastatic disease.

In cells migrating through complex three-dimensional microenvironments, microtubules are adaptively reinforced at areas of high compressive stress. This reinforcement controls the release of microtubule-bound contractility effectors to locally modify force generation in space and time, enabling motility and cell survival in mechanically strenuous settings.

Mutations in the gene encoding the E3 ubiquitin ligase TRIAD3A cause adult-onset neurodegenerative disorders. We reveal that the ubiquitin ligase activity of TRIAD3A promotes its liquid–liquid phase separation. TRIAD3A co-partitions with tau into droplets, where tau forms fibrillar aggregates. TRIAD3A mediates the degradation of these aggregates through its role as an autophagy adaptor.

Mitochondrial damage in stress conditions results in the release of mitochondrial DNA (mtDNA), causing inflammation that is linked to various diseases. We discovered a mechanism for the elimination of this harmful mtDNA — ‘nucleoid-phagy’. Targeting this process represents another way to treat mitochondrial damage-related diseases.

We show that the mitochondrial fission proteins MiD49 and MiD51 are activated by fatty acyl-coenzyme A (FA-CoA). FA-CoA binds in a previously identified pocket located within MiDs, inducing their oligomerization and ability to activate the dynamin DRP1, ultimately promoting mitochondrial fission. Activated MiDs synergize with mitochondrial fission factor (MFF) in stimulating DRP1 activity, leading us to hypothesize that MiDs act upstream of MFF during mitochondrial fission.

Contractile activity of both the epithelium and underlying mesenchyme are required for epithelial deformation and cell fate acquisition during early mouse hair follicle development. Subsequently, localized basement membrane remodelling facilitates the release of tension-generated pressure to promote cell divisions, tissue fluidification and downgrowth of the developing hair follicle.

The chemoresistant and immunoevasive characteristics of leukaemia stem cells (LSCs) impede the treatment efficacy for acute myeloid leukaemia (AML). We find that inhibiting the tyrosine phosphatase SHP-1 effectively alters the metabolic state of LSCs, making them more susceptible to chemotherapy and immune surveillance in AML.

The generation of clathrin-coated vesicles during endocytosis requires the co-ordinated recruitment of dozens of proteins to the plasma membrane. We discovered that the plant TPLATE (or TSET) complex (TPC) undergoes biomolecular condensation through interactions with plasma membrane phospholipids and, via weak multivalent interactions, recruits clathrin and other endocytic proteins to facilitate the efficient progression of endocytosis.

Lineage transitions are a central feature of prostate development, tumorigenesis and treatment resistance. We discovered that inhibition of mitochondrial pyruvate uptake results in large-scale chromatin remodelling of key lineage-specific genes, antagonizes luminal lineage identity, and alters response to antiandrogen therapy in prostate cancer.

By regulating the condensation of the molecular transport machinery coat protein complex II (COPII), manganese ions contribute to the regulation of lipoprotein secretion and thereby the circulating lipid levels.

The fibrous geometry of extracellular matrices (ECMs) is believed to facilitate cell adhesion, but a mechanistic link is lacking. We uncover a type of integrin-mediated cell adhesion — ‘curved adhesion’ — driven by the fibrous geometry of the ECM. Curved adhesions are induced by membrane curvature, enabling cell adhesion to soft three-dimensional (3D) ECM fibres.

In many species, maternally deposited Piwi-interacting RNAs (piRNAs) deliver intergenerational epigenetic information to protect progeny from transposon expansion or invasion. However, Y-chromosome-encoded piRNAs cannot be passed from mothers to male offspring, yet mothers use autosomally encoded piRNAs to allow sons to utilize their Y chromosome to protect against ‘selfish’ elements.

Genetic clearance of p16^high senescent cells or the use of senolytics improved the efficacy of stem cell reprogramming in vitro and in vivo, and helped establish induced pluripotent stem cells with features of experimental totipotency. When ablation of p16^high senescent cells was combined with partial four-factor reprogramming in vivo, we observed noticeable histopathological liver rejuvenation in aged mice.

Cells use various metabolic pathways to synthesize the building blocks for growth and proliferation. To ensure balanced growth, these biosynthetic processes must be tightly coordinated. We describe a molecular machinery that senses the cellular capacity to make lipids to regulate other biosynthetic processes — such as protein synthesis — accordingly.

Sphingomyelin synthase 2 foci assemble at the leading edge of the basal membrane in migrating cells, and these foci eventually become sites of migrasome formation. Conversion of ceramide to sphingomyelin spurs migrasome growth and preserves the structural integrity of these organelles.

Molecular insight into mechanisms that mediate the selective autophagy of lipid droplets (that is, lipophagy) has been lacking. This study identifies spartin, a protein mutated in a complex hereditary spastic paraplegia called Troyer syndrome, as a receptor that targets lipid droplets to the lysosome for degradation.

Class 3 phosphatidylinositol-3-kinase (PI3K) has a surprising nuclear function as a coactivator of the circadian clock Bmal1–Clock transcription factor complex for rhythmic purine nucleotide metabolism. This finding opens new avenues for establishing the roles of nuclear subunits of class 3 PI3K in metabolic homeostasis.

The rabbit is an important model species for developmental and translational research. Here, we used histological imaging and single-cell transcriptomics to characterize gastrulation and early organogenesis in the rabbit. We identified substantial transcriptional differences between the rabbit and mouse, highlighting the power of cross-species comparative genomics to elucidate early human development.

This study reveals that thermogenic stimuli activate mitochondrial proteolysis via LONP1 to sustain the succinate levels required for efficient conversion of white adipocytes to beige adipocytes. Our work highlights mitochondrial proteases (mitoproteases) as a link between environmental stimuli, metabolite levels and cell identity switching.