The RNA exosome nuclease complex regulates human embryonic stem cell differentiation
We report that the surveillance pathway mediated by the RNA exosome nuclease complex represses ESC differentiation. Depletion of the exosome expedites differentiation of human ESCs into all three germ layers. LINE-1 retrotransposons and specific miRNAs, lncRNAs, and mRNAs that encode developmental regulators or affect their expression are all bound by the exosome and increase in level upon exosome depletion. The exosome restrains differentiation in part by degrading transcripts encoding FOXH1, a transcription factor crucial for mesendoderm formation. Our studies establish the exosome as a regulator of human ESC differentia...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Belair, C., Sim, S., Kim, K.-Y., Tanaka, Y., Park, I.-H., and, Wolin, S. L. Tags: Stem Cells, RNA Biology, Development Articles Source Type: research
Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle
Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker H2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration throu...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Xia, Y., Pfeifer, C. R., Zhu, K., Irianto, J., Liu, D., Pannell, K., Chen, E. J., Dooling, L. J., Tobin, M. P., Wang, M., Ivanovska, I. L., Smith, L. R., Greenberg, R. A., Discher, D. E. Tags: Migration, Motility, Biophysics Articles Source Type: research
High-resolution imaging reveals how the spindle midzone impacts chromosome movement
In the spindle midzone, microtubules from opposite half-spindles form bundles between segregating chromosomes. Microtubule bundles can either push or restrict chromosome movement during anaphase in different cellular contexts, but how these activities are achieved remains poorly understood. Here, we use high-resolution live-cell imaging to analyze individual microtubule bundles, growing filaments, and chromosome movement in dividing human cells. Within bundles, filament overlap length marked by the cross-linking protein PRC1 decreases during anaphase as chromosome segregation slows. Filament ends within microtubule bundles...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Pamula, M. C., Carlini, L., Forth, S., Verma, P., Suresh, S., Legant, W. R., Khodjakov, A., Betzig, E., Kapoor, T. M. Tags: Cytoskeleton, Cell Cycle and Division Articles Source Type: research
SET binding to Sgo1 inhibits Sgo1-cohesin interactions and promotes chromosome segregation
At anaphase onset, Sgo1 function of cohesion protection must be disabled to allow timely chromosome segregation, but how this is achieved is not fully understood. Here, we show that SET, a known PP2A inhibitor, directly binds to a domain in Sgo1 in close proximity to the cohesin-binding motif. The Sgo1–cohesin binding can be disrupted by SET in a dose-dependent manner in vitro as well as by SET overexpression in cells, suggesting that SET is also an inhibitor to the Sgo1–cohesin binding. Furthermore, the SET binding–deficient Sgo1 mutant fully supports centromeric cohesion protection but delays chromosome...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Qu, Q., Zhang, Q., Yang, L., Chen, Y., Liu, H. Tags: Cell Cycle and Division Articles Source Type: research
Superresolution microscopy reveals linkages between ribosomal DNA on heterologous chromosomes
The spatial organization of the genome is enigmatic. Direct evidence of physical contacts between chromosomes and their visualization at nanoscale resolution has been limited. We used superresolution microscopy to demonstrate that ribosomal DNA (rDNA) can form linkages between chromosomes. We observed rDNA linkages in many different human cell types and demonstrated their resolution in anaphase. rDNA linkages are coated by the transcription factor UBF and their formation depends on UBF, indicating that they regularly occur between transcriptionally active loci. Overexpression of c-Myc increases rDNA transcription and the f...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Potapova, T. A., Unruh, J. R., Yu, Z., Rancati, G., Li, H., Stampfer, M. R., Gerton, J. L. Tags: Chromatin or Epigenetics, DNA Biology Articles Source Type: research
Filamin A mediates isotropic distribution of applied force across the actin network
We examined the effects of strain on force transmission through the essential cytoskeletal linker talin. Using a fluorescence-based talin tension sensor (TS), we found that uniaxial stretch of cells on elastic substrates increased tension on talin, which was unexpectedly independent of the orientation of the focal adhesions relative to the direction of strain. High-resolution electron microscopy of the actin cytoskeleton revealed that stress fibers (SFs) are integrated into an isotropic network of cortical actin filaments in which filamin A (FlnA) localizes preferentially to points of intersection between SFs and cortical ...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Kumar, A., Shutova, M. S., Tanaka, K., Iwamoto, D. V., Calderwood, D. A., Svitkina, T. M., Schwartz, M. A. Tags: Cytoskeleton, Biophysics Reports Source Type: research
LTK is an ER-resident receptor tyrosine kinase that regulates secretion
The endoplasmic reticulum (ER) is a key regulator of cellular proteostasis because it controls folding, sorting, and degradation of secretory proteins. Much has been learned about how environmentally triggered signaling pathways regulate ER function, but only little is known about local signaling at the ER. The identification of ER-resident signaling molecules will help gain a deeper understanding of the regulation of ER function and thus of proteostasis. Here, we show that leukocyte tyrosine kinase (LTK) is an ER-resident receptor tyrosine kinase. Depletion of LTK as well as its pharmacologic inhibition reduces the number...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Centonze, F. G., Reiterer, V., Nalbach, K., Saito, K., Pawlowski, K., Behrends, C., Farhan, H. Tags: Cell Signaling, Trafficking, Biochemistry Reports Source Type: research
Beyond proteases: Basement membrane mechanics and cancer invasion
In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM. However, recent studies point toward a more complex picture, with physical forces generated by cancer ce...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Chang, J., Chaudhuri, O. Tags: Migration, Motility, Biophysics, Cancer Review Source Type: research
Assembling nuclear domains: Lessons from DNA repair
Eukaryotic nuclei are organized into nuclear domains that unite loci sharing a common function. These domains are essential for diverse processes including (1) the formation of topologically associated domains (TADs) that coordinate replication and transcription, (2) the formation of specialized transcription and splicing factories, and (3) the clustering of DNA double-strand breaks (DSBs), which concentrates damaged DNA for repair. The generation of nuclear domains requires forces that are beginning to be identified. In the case of DNA DSBs, DNA movement and clustering are driven by actin filament nucleators. Furthermore,...
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Schrank, B., Gautier, J. Tags: DNA Biology, Biochemistry Review Source Type: research
Neurexin nanoclusters: A novel structure at presynaptic terminals
The trans-synaptic cell adhesion molecule neurexin regulates synaptic functions but its high-resolution subcellular localization and dynamics were unknown. Trotter et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201812076) describe previously unrecognized nanoscale clusters of neurexin-1 in presynaptic terminals and their regulation by ADAM10-mediated proteolysis. (Source: Journal of Cell Biology)
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Kawaguchi, D., Gotoh, Y. Tags: Spotlight Source Type: research
Spastin joins LDs and peroxisomes in the interorganelle contact ballet
Lipid droplets (LDs) store energy-rich fatty acids (FAs), but to harvest them, LDs donate FAs to peroxisomes for oxidation. In this issue, Chang et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201902061) identify M1 Spastin as an LD–peroxisome tether that interacts with ESCRT-III components to facilitate lipid exchange between these two organelles. (Source: Journal of Cell Biology)
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Henne, W. M. Tags: Organelles, Membrane and Lipid Biology, Biochemistry, Metabolism Spotlight Source Type: research
A precision RNA degradation machinery shapes stem cell development
In this issue, Belair et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201811148) show that, together with a complex network of transcription factors and chromatin modifiers, the RNA exosome regulates embryonic stem cell (ESC) differentiation and pluripotency. (Source: Journal of Cell Biology)
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: Pereira, P., Arraiano, C. M. Tags: Spotlight Source Type: research
Efrain E. Rivera-Serrano: Personal training for scientists
Rivera-Serrano investigates the host cell genes that support viral infection. (Source: Journal of Cell Biology)
Source: Journal of Cell Biology - August 4, 2019 Category: Cytology Authors: ODonnell, M. A. Tags: People & amp;amp; Ideas Source Type: research
A tensile trilayered cytoskeletal endotube drives capillary-like lumenogenesis
Unicellular tubes are components of internal organs and capillaries. It is unclear how they meet the architectural challenge to extend a centered intracellular lumen of uniform diameter. In an RNAi-based Caenorhabditis elegans screen, we identified three intermediate filaments (IFs)—IFA-4, IFB-1, and IFC-2—as interactors of the lumenal membrane-actin linker ERM-1 in excretory-canal tubulogenesis. We find that IFs, generally thought to affect morphogenesis indirectly by maintaining tissue integrity, directly promote lumenogenesis in this capillary-like single-cell tube. We show that ERM-1, ACT-5/actin, and TBB-2...
Source: Journal of Cell Biology - June 30, 2019 Category: Cytology Authors: Khan, L. A., Jafari, G., Zhang, N., Membreno, E., Yan, S., Zhang, H., Gobel, V. Tags: Cytoskeleton, Development Articles Source Type: research
ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development
We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-β1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL–ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanis...
Source: Journal of Cell Biology - June 30, 2019 Category: Cytology Authors: Osorio, L., Wu, X., Wang, L., Jiang, Z., Neideck, C., Sheng, G., Zhou, Z. Tags: Adhesion, Cell Signaling, Biochemistry, Development Articles Source Type: research
