ON THE COVER
The collagen trail: Journey to the microenvironment. Ovarian cancer cell migrating along a collagen fiber, imaged using scanning electron microscopy. Image © Elizabeth Harper, University of Notre Dame, Notre Dame, IN
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People & Ideas
Dormann highlights work from Celetti and colleagues that demonstrates liquid–liquid phase separation of FG-nucleoporins into droplets that mimic the nuclear pore permeability barrier.
Renne and Emerling highlight work from Du et al. showing that ORP5 mediates lipid droplet PI(4)P levels and discuss implications for phosphoinositide signaling.
Perturbations in cellular metabolism are ubiquitous in cancer. Here Reina-Campos et al. review the role of one-carbon metabolism in tumorigenesis.
Towers et al. review the complex roles of autophagy in cancer and how autophagy relates to mechanisms of cancer cell death and tumor immunology.
Nguyen and Spranger discuss how signaling pathways within tumor cells establish tumor microenvironments that exclude tumor-reactive CD8+ T cells, leading to tumor-immune evasion.
Buffone and Weaver discuss how the structure of the backbones and glycans of the tumor glycocalyx governs cell–matrix interactions and directs cancer progression.
Many active genes position near nuclear speckles. Kim et al. show that Hsp70 speckle association correlates with increased nascent transcripts. Live-cell imaging shows that increases in nascent Hsp70 transcripts strictly follow speckle association (∼0–2 min), suggesting that speckle association amplifies gene expression.
The liquid state of FG-nucleoporins mimics permeability barrier properties of nuclear pore complexes
Nuclear pore complexes form a permeability barrier in vivo that regulates nucleocytoplasmic transport. Here, the authors present a microfluidic device that couples rapid liquid–liquid phase separation of nucleoporins with direct optical interrogation. Freshly formed liquid nucleoporin droplets mimic permeability barrier properties of NPCs.
Soh et al. study the organization of Tetrahymena ciliary arrays. Basal body–associated striated fibers organize motile cilia by promoting basal body orientation, reorientation, and resistance to ciliary forces. To do so, striated fiber length is modulated to ensure connections between neighboring basal bodies and to the cell cortex.
To prevent chromosome missegregation, a metaphase checkpoint is activated when topoisomerase II is catalytically inhibited and DNA catenations persist. Pandey et al. dissect the key molecular events triggering this regulatory system.
Lipid droplets (LDs) are important organelles for cell metabolism. Here, Du et al. show that phosphatidylinositol-4-phosphate produced by PI4K2A can exist on LDs and is used/consumed by ORP5, which localizes to ER–LD contacts during the growth of LDs.
Park et al. identify a role for a subset of mRNA splicing factors, including WBP11, in centriole biogenesis. WBP11 is required for the splicing of short, weak introns, including those found in TUBGCP6 pre-mRNA. Splicing of TUBGCP6, as well as other WBP11 targets, allows for faithful mitotic progression and centriole duplication.
CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis
Blood glucose clearance relies on insulin-stimulated exocytosis of glucose transporter 4 (GLUT4) from sites of sequestration in muscle and fat. This work demonstrates that, in humans, CHC22 clathrin controls GLUT4 traffic from the ER-to-Golgi intermediate compartment to sites of sequestration during GLUT4 pathway biogenesis.
Larocque et al. discover a new class of transport vesicles in human cells termed intracellular nanovesicles. These small carriers are defined by the presence of TPD54, an abundant yet poorly characterized protein.
This study reveals that PQLC2, a lysosomal transporter of cationic amino acids, coordinates cellular responses to cationic amino acid availability via the regulated recruitment of a heterotrimeric protein complex containing C9orf72, SMCR8, and WDR41 to the surface of lysosomes.
NCAM regulates temporal specification of neural progenitor cells via profilin2 during corticogenesis
The role of NCAM in corticogenesis is incompletely understood. The authors demonstrate that NCAM controls NPC proliferation and fate decision through profilin2-dependent regulation of actin polymerization. This finding sheds new light on NCAM’s functions in neurodevelopmental and mental disorders.
Talin and vinculin control mechanosensing by linking adhesion receptors to the contractile actin cytoskeleton. Using a mitochondrial targeting system, Atherton et al. elucidate mechanisms regulating conformational changes required for vinculin binding to talin. Such activation mechanisms are not required for either protein to interact with the adhesion regulatory protein paxillin.
Greenan et al. use electron cryotomography on intact motile cilia to elucidate how basal bodies template the formation of motile axonemes.
Szikora et al. use superresolution microscopy to reveal muscle protein localizations at the nanoscale level. With this protein localization atlas and template-based protein structure modeling, they assemble refined I-band and H-zone models and provide new mechanistic insights into sarcomerogenesis.
In pituitary cells, internalized somatostatin receptor is held in a GLUT4-like storage compartment. The receptor rapidly resurfaces in response to selective signaling pathways in a process that fine-tunes pituitary hormone release.
Recycling of MT-MMPs to actin-rich membrane-protrusive structures promotes breast cancer invasion. This study shows that SNX27–retromer, an endosomal sorting and recycling machinery, interacts with MT1-MMP and regulates its transport to the cell surface, thus promoting matrix invasive activity of the breast cancer cells.
ALK4 coordinates extracellular and intrinsic signals to regulate development of cortical somatostatin interneurons
Göngrich et al. show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. They find that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.
The cryo-EM structure of the complete insulin receptor ectodomain saturated with four insulin ligands reveals a T-like conformation with converging membrane-proximal domains and structural evidence of insulin binding sites 2/2′.
Epithelial cells are categorized as cuboidal versus squamous based on the height of the lateral membrane. Wang and Brieher show that CD2AP links PI3K activity to actin assembly to extend the height of the lateral membrane.
Ca2+ transients in melanocyte dendrites and dendritic spine-like structures evoked by cell-to-cell signaling
Belote and Simon show that melanocytes generate localized Ca2+ transients in their dendrites and dendritic spine-like structures in response to ET1 and ACh from neighboring keratinocytes. Electron microscopy of intact human skin confirms the presence of melanocyte dendritic spine-like structures as well as pooled vesicles in keratinocytes at sites of keratinocyte–melanocyte contact.
Boyer et al. describe reversible nondegradative ubiquitination of the actin polymerase VASP, mediated by a pair of E3 ubiquitin ligases TRIM9 and TRIM67. VASP regulation is necessary for responses of filopodia, growth cones, and axons to the guidance cue netrin-1.
Coupling APEX labeling to imaging mass spectrometry of single organelles reveals heterogeneity in lysosomal protein turnover
Narendra et al. demonstrate that APEX can be used as the first genetically encoded reporter for isotope ratio imaging mass spectrometry. Bulk protein turnover is measured in individual lysosomes demonstrating unanticipated heterogeneity among lysosomes within a single cell.