On the cover
Shown is an individual myofiber dissected from the tibialis anterior muscle of a day 18.5 mouse embryo lacking Nesprin 1α2 and stained for the nuclear lamin protein Lamin A/C (green), sarcomeric α-actinin (red), and DAPI (blue). Image © 2017 Stroud et al.
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People & Ideas
María Gómez previews work by Müller and Nieduszynski that describes a biological role for conserved replication timing differences in eukaryotic cells.
Price previews work from the Miller laboratory identifying the H3K4 histone demethylase KDM5A as promoting double-stranded DNA break repair.
Hammarskjold and Rekosh preview new results from the Müller-McNicoll laboratory suggesting that the differentiation state modulates SR protein nucleocytoplasmic shuttling and function.
Maedler and Ardestani discuss recent work from Chau et al. on the role of mTOR for β cell survival in diabetes.
The functions of four of the five proteins in the mammalian uncoordinated-13 (Munc13) family have been identified as priming factors in SNARE-dependent exocytosis. In this issue, Zhang et al. show that the fifth member, BAIAP3, acts in retrograde trafficking by returning secretory vesicle material to the TGN. In its absence, secretory vesicle formation is impaired, leading to accumulation of immature vesicles, or lysosomal vesicle degradation.
Vijayan and Verstreken review the process of autophagy in the synapse and the role of autophagy in maintaining neuronal function.
Eukaryotic genomes are replicated in a reproducible temporal order whose physiological significance is poorly understood. Müller and Nieduszynski compare the temporal order of genome replication in phylogenetically diverse yeast species and identify genes for which conserved replication timing contributes to maximal expression.
Defects in nuclear positioning occur in muscle diseases and correlate with muscle dysfunction. In this study, Stroud et al. show that nesprin 1α2 is the fundamental nesprin 1 isoform for nuclear positioning, skeletal muscle function, and postnatal viability.
Concerted actions of distinct nonmuscle myosin II isoforms drive intracellular membrane remodeling in live animals
Using intravital subcellular microscopy, Milberg et al. show that distinct but coordinated activities of two different nonmuscle myosin II isoforms drive the integration of large secretory granules into the plasma membrane during regulated exocytosis in live mice.
Rab7 promotes fusion of autophagosomes and late endosomes with lysosomes. Lőrincz et al. show that Rab2 is critical for the delivery of autophagic and endocytic cargo to lysosomes and for their degradation, and that it promotes autophagosome–lysosome fusion. The results suggest Rab2 and Rab7 coordinately promote autophagic and endosomal degradation and lysosome function.
Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing
It is unclear how mTORC1 signaling differs in senescent and young cells. Carroll et al. show that senescence leads to constitutive mTORC1 activation and resistance to serum and amino acid starvation. This is associated with elevated autophagy, depolarization of cell plasma membrane, and primary cilia defects.
Upon DNA damage, histone modifications are reshaped to accommodate DNA damage signaling and repair. Gong et al. report that the histone demethylase KDM5A promotes loading of the chromatin remodeling complex ZMYND8–NuRD to double-strand DNA breaks through H3K4me3 demethylation, thereby allowing repair of the lesion.
Histone chaperone HIRA regulates neural progenitor cell proliferation and neurogenesis via β-catenin
Histone cell cycle regulator (HIRA) is a histone chaperone that plays a critical role in epigenetic regulation. Li and Jiao show that HIRA regulates various aspects of neural development, including neural progenitor cell distribution, proliferation, and differentiation via a mechanism that involves recruitment of the H3K4 methyltransferase Setd1A to the β-catenin promoter.
SR proteins connect nuclear pre-mRNA processing to mRNA export and translation. Botti et al. develop a quantitative nucleocytoplasmic shuttling assay and show that SR proteins are differentially modified and active in differentiated and pluripotent cells.
RAS association domain family 4 (RASSF4) is involved in tumorigenesis. Chen et al. show that RASSF4 regulates store-operated Ca2+ entry and ER–PM junctions by affecting PI(4,5)P2 levels. RASSF4 interacts with and regulates the activity of ARF6, an upstream regulator of PIP5K and PI(4,5)P2.
Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals
Mitochondrial stress activates a concerted mitonuclear response to safeguard and repair mitochondrial function. Quirós et al. assessed the transcriptome, proteome, and metabolome of mammalian cells under four types of stressors and combine population genetic analyses and in vivo studies to show that ATF4 coordinates the mitochondrial stress response.
Accurate spindle positioning depends on the action of the dynein motor protein at microtubules. Estrem et al. now show that increased dynein-mediated activity destabilizes microtubules by displacing dynactin from the plus end and suggests that the interplay between these opposing effects on microtubule stability at the cortex is required to move the spindle to the correct position.
Using proteomics, live microscopy, and superresolution microscopy, Ganguly et al. offer insight into the molecular composition of cytosolic cargo complexes conveyed in slow axonal transport, identifying the heat shock protein Hsc70 as a major regulator of this transport.
Adaptation to stress is a critical strategy for all life. Known strategies involve signaling pathways that induce changes in gene expression. These changes take time and cannot protect against acute assaults. Jin et al. reveal an early stress protection pathway regulated by the vacuole/lysosome.
Through in vivo analyses of mTOR deficiency and in vitro studies of human and mouse pancreatic islets, Chau et al. show that mTOR plays a critical role in β cell survival in diabetes. mTOR associates with and inhibits the transcriptional ChREBP–Mlx complex, suppressing TXNIP expression and β cell death.
TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1
Genova et al. describe a novel non-channel function for the endogenous TRPM8 as a negative regulator of Rap1 GTPase. TRPM8 retains Rap1GDP intracellularly thus resulting in altered behavior of vascular endothelial cell adhesion and migration.
Monis et al. demonstrate that the BLOC-1 protein complex is required for trafficking polycystin-2, but not fibrocystin or smoothened, from endosomes to primary cilia. This is the first demonstration of a role for BLOC-1 in ciliary assembly and emphasizes the complexity of distinct ciliary membrane protein trafficking routes.
BAIAP3, a C2 domain–containing Munc13 protein, controls the fate of dense-core vesicles in neuroendocrine cells
Zhang et al. conducted a siRNA screen of C2 domain proteins involved in regulated peptide secretion. One of the hits, a Munc13 family member BAIAP3, was characterized as endosome localized involved in post-exocytic dense-core vesicle protein recycling to the TGN. BAIAP3 knockdown inhibited dense-core vesicle maturation/stability in neuroendocrine/endocrine cells.
ESCRT proteins play essential functions by remodeling cellular membranes. Buono et al. report on a novel ESCRT-dependent mechanism in plant endosomes that leads to sequential concatenation of vesicle buds by temporally uncoupling membrane constriction from membrane fission. During this process, ESCRT-III proteins remain inside endosomes after intralumenal vesicle release.
Little is known about central neuron mechanosensation. Gu et al. report that micromechanical stress preferentially induces rapid and reversible varicosity formation in the axons but not the dendrites of hippocampal neurons through activation of mechanosensitive ion channels and microtubule disassembly.
Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells
Lysyl-tRNA synthetase (KRS) can be released from cancer cells to cause inflammation, but the mechanism of KRS secretion is unknown. Kim et al. demonstrate that KRS is cleaved by caspase-8, which exposes a binding motif for syntenin and facilitates the secretion of KRS in exosomes.
Extracellular vesicles (EVs) are emerging as crucial mediators in cell-to-cell communication. Stik et al. provide evidence that EVs released by supportive stromal cells target hematopoietic stem and progenitor cells in vivo and in vitro and influence their gene expression and potential.