On the cover
Maximum intensity projection of a cancer cell spheroid and cancer-associated fibroblasts (CAFs). CT26 cancer cells express LifeAct-GFP (blue) and F-actin is stained with phalloidin-rhodamin. Both channels are subtracted using ImageJ (NIH) to show F-actin only in CAFs (yellow) and the image was processed on IMARIS software using Blend mode. Image © 2017 Attieh et al.
See page 3509.
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People & Ideas
Rowe and colleagues preview work from Cuellar et al. that identifies SETDB1 as a repressor of immunostimulatory retrotransposons in leukemia.
Chamberland and Ritter discuss work from Kvainickas et al. and Simonetti et al. demonstrating a retromer-independent function of SNX-BAR proteins in endosomal recycling.
Machesky and Braga preview work from the Gottardi laboratory exploring the role of a new interaction between α-catenin homodimers and PIP3 in cell adhesion.
Norton and Phillips-Cremins review the 3D architecture of the genome and discuss links between chromatin misfolding and human diseases.
NuMA has been suggested to function as a Ran-regulated spindle assembly factor that modulates spindle pole assembly. Chang et al. provide structural and biochemical evidence showing that NuMA contains an Importin-β–regulated microtubule-binding region, which allows Ran to regulate the NuMA functions required for the assembly of higher-order microtubule structures.
In budding yeast, cell size is thought to be primarily controlled by a mechanism that delays cell cycle entry until sufficient growth has occurred in G1. Leitao and Kellogg show that nutrients modulate cell size by controlling the amount of growth that occurs during mitosis.
TORC1 signaling exerts spatial control over microtubule dynamics by promoting nuclear export of Stu2
TORC1 regulates microtubule (MT) dynamics in budding yeast, but the key downstream effectors are unknown. van der Vaart et al. show that TORC1 activity before mitosis promotes phosphorylation of the MT polymerase Stu2 near a nuclear export signal, which leads to the nuclear export of Stu2 and reduced nuclear MT growth.
Channels in the mitochondrial outer membrane exchange metabolites, ions, and proteins with the rest of the cell. Kruger et al. identify several new types of channel and suggest that the outer mitochondrial membrane is a more selective molecular sieve with a greater variety of channel-forming proteins than previously appreciated.
Neppl et al. identify a long noncoding RNA named Chronos whose expression increases with age and decreases in Akt-mediated growth. Inhibition of Chronos induces myofiber hypertrophy in vitro and in vivo, in part, through the epigenetic modulation of Bmp7 signaling.
Cancer-associated fibroblasts lead tumor invasion through integrin-β3–dependent fibronectin assembly
Cancer-associated fibroblasts (CAFs) promote cancer cell invasion and dissemination by remodeling the extracellular matrix; however, the mechanism by which CAFs remodel the matrix is still unknown. Attieh et al. show that CAFs induce cancer cell invasion through fibronectin matrix assembly that is mainly mediated by integrin-αvβ3.
The DNA helicase BLM can have both pro- and anti-recombination effects. Patel et al. show that in cells lacking the homologous recombination repair factors BRCA1, XRCC2, or BRCA2, BLM prevents the assembly of stable RAD51 nucleoprotein filaments, leading to genomic instability and reduced cell viability.
Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia
Cancer cells can rewire genetic and epigenetic regulatory networks to promote cell proliferation and evade the immune system. Using a focused CRISPR/Cas9 genetic screen, Cuellar et al. identify a novel role for the SETDB1 histone methyltransferase in regulating the antiviral response in AML cells via the suppression of transposable elements.
Dhatchinamoorthy et al. use calibrated imaging, FRAP, and photoconversion to study the changes in kinetochore component copy numbers from G1 to anaphase and find that the Dam1 submodule is unchanged during anaphase, whereas MIND and Ndc80 submodules add copies, providing insight into the dynamics and plasticity of the kinetochore structure during chromosome segregation.
Establishing the spindle in mammalian oocytes after their prolonged arrest occurs in the absence of centrioles and is crucial for meiotic fidelity. Bury et al. show that this requires concerted activity of microtubule organizing center–associated Aurora A and Plk4, which are usually found at centrioles.
The fission yeast nucleoporin Alm1 is required for proteasomal degradation of kinetochore components
TPR nucleoporins form the nuclear pore complex basket. The fission yeast TPR Alm1 is required for localization of the proteasome to the nuclear envelope, which is in turn required for kinetochore homeostasis and proper chromosome segregation.
Kapinos et al. show that nuclear pore complex permeability and cargo release functionalities are concomitantly regulated by karyopherin occupancy and turnover in a systematic continuum. This highlights increasingly important roles for the soluble nucleocytoplasmic transport machinery that depart from established views of the nuclear pore complex selectivity mechanism.
The STT3A isoform of the oligosaccharyltransferase is adjacent to the protein translocation channel to catalyze co-translational N-glycosylation of proteins in the endoplasmic reticulum. Shrimal et al. show that the DC2 and KCP2 subunits of the STT3A isoform of the oligosaccharyltransferase are responsible for mediating the interaction between the STT3A complex and the protein translocation channel to allow co-translational N-glycosylation of proteins.
Proteins are thought to be delivered to the bacterial plasma membrane cotranslationally by signal recognition particle or posttranslationally by SecA. Wang et al. identify a new membrane protein–targeting pathway in bacteria in which SecA cotranslationally recognizes and targets the inner membrane protein RodZ, which harbors an internal transmembrane domain.
The pan-kinase inhibitor foretinib is identified as a potent suppressor of sympathetic, sensory, and motor neuron axon degeneration, acting in part by inhibiting the activity of the unliganded TrkA/nerve growth factor receptor and by preserving mitochondria in die-back and Wallerian degeneration models.
Kvainickas et al. show that the retromer cargo CI-MPR does not recycle from endosomes to the trans-Golgi network through interactions with the core retromer trimer. Instead, CI-MPR depends on cargo-selective SNX-BAR proteins, which function independently of the core retromer trimer.
By revisiting the classical role of retromer in endosomal sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR), Simonetti et al. reveal that CI-MPR sorting actually occurs via SNX1/2–SNX5/6 membrane-tubulating complexes, thereby reappraising retromer’s role in this important transport process.
The classical view of centrosome decentering and migration to the cell periphery during ciliogenesis is that it is pulled toward its final destination. Here, Pitaval et al. argue that microtubule stabilization in the early stages of ciliogenesis generates pushing forces that propel the centrosome toward the apical pole.
Adherens junction remodeling allows changes in cell shape and position. Zilberman et al. show through live imaging that CDC-42 is dispensable for epithelial cell polarization, but its RhoGAP-regulated activity is needed to control junctional actin organization during embryo elongation.
Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature
How the membrane environment informs when and where actin is polymerized in clathrin-mediated endocytosis is unclear. Daste et al. show that high membrane curvature stimulates PI(3,4)P2 dephosphorylation by INPP4A and that PI(3)P recruits SNX9 in conjunction with both PI(4,5)P2 and high membrane curvature. Furthermore, they find that Lowe syndrome mimics this membrane microenvironment with the aberrant formation of a PI(4,5)P2/PI(3)P intermediate, giving rise to actin comets.
Wood et al. show that α-catenin homodimers, but not monomers, selectively bind phosphatidylinositol-3,4,5-trisphosphate–containing vesicles with high affinity in vitro in a cadherin-independent manner and that cadherin-free α-catenin is recruited to the leading edge of migrating cells in a phosphatidylinositol 3-kinase–dependent manner to promote adhesion and migration.
Kindlin-2 recruits paxillin and Arp2/3 to promote membrane protrusions during initial cell spreading
Cell spreading relies on the coordinated and dynamic regulation of integrin-mediated adhesions and actin structures. Böttcher et al. show that in the periphery of adhering cells kindlin-2 binds paxillin to activate Rac1 and the Arp2/3 complex to allow for Rac1-mediated membrane protrusions.
Cancer-associated fibroblasts (CAFs) in the tumor stroma play a key role in tumor progression. Erdogan et al. show that CAF-mediated alignment of the fibronectin matrix is a key factor promoting directional cancer cell migration.
A novel intracellular pool of LFA-1 is critical for asymmetric CD8+ T cell activation and differentiation
LFA-1 mediates T cell migration and their stable interaction with antigen-presenting cells, but how intracellular LFA-1 dynamically and spatially regulates T cell function is unclear. Capece et al. now demonstrate that intracellular LFA-1 in naive CD8+ T cells controls their asymmetric activation and differentiation into effector or memory T cells.
Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly
Hippocampal CA1 region neurons specifically target latrophilin-2 (Lphn2), an adhesion-type GPCR, to dendritic spines in the stratum lacunosum-moleculare. In this study, Lphn2 controls assembly of excitatory synapses formed by presynaptic entorhinal cortex afferents but not by Schaffer-collateral afferents, suggesting a synaptic recognition function.
Cell–cell adhesion accounts for the different orientation of columnar and hepatocytic cell divisions
In this study, the authors examine the mechanisms that regulate the different orientation of the cell division axis between monolayered MDCK cells and bilayered hepatocytic cells. They determine that hepatocytic cells, which feature out-of-monolayer divisions, lack a Rho- and E-cadherin–dependent mechanism mediating the anaphase cell flattening that aligns mitotic spindles with the substratum in MDCK cells.
The authors show that the heterodimeric capping protein subunit CAPZB is required during development of stereocilia, actin-filled processes of the inner ear. They find that CAPZB prevents depolymerization of newly formed actin filaments during the developmental stage when stereocilia widen.