ON THE COVER
A junction between two endothelial cells (dark blue and green) is maintained by colliding branched actin networks from both cells labeled by immunogold against VE-cadherin (yellow) and Arp2/3 complex (red). The strip of branched actin is linked to the rest of the cytoskeleton by oblique actin filaments (purple and blue).
Image © Efimova et al., 2018.
See page 1827.
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Seeing the insulin receptor in action
Researchers use single-particle electron microscopy to visualize an insulin-induced conformational shift that leads to receptor activation.
People & Ideas
Johan Auwerx: Sowing the seeds of translational research
Auwerx studies the signaling networks that underlie mitochondrial function and metabolism.
Dynamic visits of cortical structures probe for cell size
Gerganova and Martin preview work from Allard et al. that describes the Wee1- and Cdr1/2-dependent mechanism by which cells link cell size with mitotic entry.
DNA replication licensing in stem cells: Gatekeeping the commitment to proliferation
Coller previews work from the Carroll et al. identifying proliferative intestinal stem cells in an unlicensed state, providing insight into what controls the transition between quiescence and proliferation.
Light sheet imaging comes of age
Watkins and St. Croix outline light-sheet imaging techniques and position the new “LITE microscopy” from Fadero et al. within this increasingly vital platform.
Mechanotransduction in tumor progression: The dark side of the force
Broders-Bondon et al. review the pathological mechanical properties of tumor tissues and how abnormal mechanical signals result in oncogenic biochemical signals during tumor progression.
Cell size–dependent regulation of Wee1 localization by Cdr2 cortical nodes
Cells turn off the mitotic inhibitor Wee1 to enter into mitosis. Allard et al. show how cell growth progressively inhibits fission yeast Wee1 through dynamic bursts of localization to cortical node structures that contain Wee1 inhibitory kinases.
Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation
Medeiros et al. show that mtDNA polymerase POLG controls mtDNA copy number in the context of autophagy-mediated metabolic homeostasis. After prolonged starvation, the mtDNA degradative activity of POLG is activated to adjust the increasing mtDNA copy number in WT cells, whereas in autophagy-deficient cells, POLG’s continued degradative activity causes mtDNA instability and respiratory dysfunction as a result of nucleotide insufficiency.
Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin
PINK1/parkin are key mediators of stress-induced mitophagy in vitro, but their impact on basal mitophagy in vivo is unclear. Novel Drosophila reporter lines reveal abundant mitophagy in many tissues, including dopaminergic neurons, that is unaffected by loss of PINK1/parkin.
Membrane protein recycling from the vacuole/lysosome membrane
How membrane proteins delivered to the vacuole membrane are recycled remains unknown. Suzuki and Emr show that the Snx4 coat complex assembles on the vacuole surface to mediate the vacuole-to-endosome retrograde trafficking of transmembrane proteins.
CLAMP/Spef1 regulates planar cell polarity signaling and asymmetric microtubule accumulation in the Xenopus ciliated epithelia
Kim et al. show that CLAMP regulates planar cell polarity (PCP) signaling. Its depletion causes a loss of the atypical cadherin Celsr2, a loss of PCP protein asymmetry, and a defect in cilia polarity and oriented cell division. CLAMP also, via its role in PCP, regulates the accumulation of an asymmetric pool of microtubules.
Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor
Using single-particle electron microscopy of the human insulin receptor reconstituted into nanosdiscs, Gutmann et al. show that ligand binding induces a conformational rearrangement in the receptor ectodomain that results in the dimerization of the transmembrane domains and receptor activation.
Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression
How endothelial cells sense and react to flow during vascular remodeling is poorly understood. Vion et al. show that endothelial cells utilize their primary cilia to stabilize vessel connections during vascular remodeling. Molecularly, they identify enhanced sensitivity to BMP9 in ciliated endothelial cells, selectively under low flow.
Lgr5+ intestinal stem cells reside in an unlicensed G1 phase
Cell cycles of intestinal stem and transit-amplifying cells are poorly understood. Comparing total and DNA-bound Mcm2 in intact intestinal crypts, Carroll et al. show that most stem cells reside for long periods in the unlicensed G1 phase. In the unlicensed G1 phase, stem cells could interpret cues before resuming cell division.
Kinesins relocalize the chromosomal passenger complex to the midzone for spindle disassembly
The chromosomal passenger complex (CPC) is a master mitotic regulator, but its role during mitotic exit is not fully understood. Ibarlucea-Benitez et al. reveal that the kinesins Kip1 and Kip3 recruit the CPC to the spindle midzone in anaphase and show that this relocalization is important for spindle disassembly.
PDGFRβ translocates to the nucleus and regulates chromatin remodeling via TATA element–modifying factor 1
PDGFRβ translocates to the nucleus in a ligand-dependent manner tethered by TATA element–modifying factor 1 (TMF-1). Papadopoulos et al. show that PDGFRβ interacts with TMF-1 and Fer kinase in the nucleus, regulating chromatin remodeling by the SWI–SNF complex and controlling proliferation via a p21-dependent mechanism.
Motor axon navigation relies on Fidgetin-like 1–driven microtubule plus end dynamics
Fassier et al. identify Fidgetin-like 1 (Fignl1) as a key growth cone (GC)-enriched microtubule (MT)-associated protein in motor circuit wiring. They show that Fignl1 modulates motor GC morphology and steering behavior by down-regulating EB binding at MT plus ends and promoting MT depolymerization beneath the cell cortex.
Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization
Phosphorylation of IRE1 at S729 enhances splicing of XBP1 messenger RNA and regulates RIDD. lipopolysaccharide-stimulated plasmablasts from S729A knock-in mice fail to boost spliced XBP1 in response to ER stress. Such mice exhibit plasma cells with decreased numbers and altered functions after immunization.
Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation
Cells are thought to adapt to proteasome inhibition by using alternative pathways for degradation such as autophagy. Sha et al. now report that cells rapidly induce GABARAPL1 and p62 upon proteasome inhibition, but this promotes cell survival by sequestering ubiquitinated and sumoylated proteins long before the cells induce other Atg genes and activate autophagy.
The Rab11-binding protein RELCH/KIAA1468 controls intracellular cholesterol distribution
Sobajima et al. identify the novel protein RELCH/KIAA1468 as a Rab11-binding protein and show that RELCH/KIAA1468 and Rab11 regulate OSBP-dependent nonvesicular cholesterol transport from recycling endosomes to the trans-Golgi network.
PI(4,5)P2 controls plasma membrane PI4P and PS levels via ORP5/8 recruitment to ER–PM contact sites
Sohn et al. show that plasma membrane PI(4,5)P2 controls the level of its precursor, PI4P, by regulating PI4P/PS exchange activity of ORP5/8. This control is achieved via regulation of ORP5/8 interaction with the plasma membrane by both of these phosphoinositides.
Feedback inhibition of actin on Rho mediates content release from large secretory vesicles
This work identified a cycle of actin assembly and disassembly in large secretory vesicles of Drosophila salivary glands. Actin disassembly is triggered by actin-dependent recruitment of a RhoGAP protein and is essential for the contractility of the vesicle, leading to content release to the lumen.
Branched actin networks push against each other at adherens junctions to maintain cell–cell adhesion
The actin cytoskeleton at adherens junctions acts as a dynamic push–pull system, wherein pushing forces generated in both contacting cells through Arp2/3 complex–dependent actin polymerization maintain cadherin transinteraction in the extracellular gap, whereas pulling forces stabilize intercellular adhesion complexes.
BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone
Upon activation, GPCRs must exit cilia for appropriate signal transduction. Using bulk imaging of BBSome and single-molecule imaging of GPCRs, Ye et al. demonstrate that retrograde BBSome trains assemble on demand upon GPCR activation and ferry GPCRs across the transition zone. However, ciliary exit often fails because of a second diffusion barrier.
LITE microscopy: Tilted light-sheet excitation of model organisms offers high resolution and low photobleaching
Fadero et al. present lateral interference tilted excitation (LITE) microscopy–a tilted light-sheet method to illuminate high-numerical-aperture objectives for fluorescence microscopy. LITE can be implemented unobtrusively on most microscope systems and combines low photodamage with high resolution and efficient detection in imaging fluorescent organisms.