On the cover
Lysosomal voltage-dependent K+ channels are activated by cytosolic Ca2+ when lysosomal Ca2+ stores are depleted. The activation of K+ lysosomal channels results in K+ influx and depolarization of lysosomal membrane potential. Subsequently, endoplasmic reticulum (ER) tubules will attach to form ER–lysosome contact sites, refilling Ca2+ to lysosomes. Original artwork by Felichi Mae Arines and Yexin Yang. Image © 2017 Arines and Yang
See Wang et al., page 1715.
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People & Ideas
Mizutani et al. preview the study by Riemer et al. that uses intestinal organoids to show that PI3K and β-catenin signaling modulates several phenotypes of cancer cells.
Titus and Goodson preview work from the Mullins group analyzing the determinants of amoeboid motility with an evolutionary approach.
Zhu discusses work on organeller ion transporters from Wang et al. describing the importance of a lysosomal voltage-sensitive Ca2+-activated K+ channel.
O’Byrne and Richard preview results from the Bouchier-Hayes group delineating two distinct pathways for caspase-2 activation in response to different stimuli
Spindle assembly checkpoint satisfaction occurs via end-on but not lateral attachments under tension
The spindle assembly checkpoint (SAC) delays anaphase until kinetochores are properly attached to the spindle. Kuhn and Dumont demonstrate that the mammalian SAC monitors geometry-specific molecular cues or force on specific kinetochore linkages that end-on but not lateral attachments generating persistent tension can provide.
Effective collective cell migration depends on delicate tuning of cell motility forces and cell–cell communication. Zaritsky, Tseng, and coworkers identified differential roles for RhoA, RhoC, and their upstream activators in mediating long-range transmission of guidance cues.
Myosin V–mediated cargo transport ensures that organelles are correctly positioned in cells, an essential process for cellular function. In this study, Yau et al. show that the p21-activated kinase Cla4 spatially regulates the release of a myosin V cargo.
Oncogenic β-catenin and PIK3CA instruct network states and cancer phenotypes in intestinal organoids
Organoids are stem cell–driven 3D tissue cultures. Riemer et al. find that activation of β-catenin and PI3K signaling induces multiple cancer traits in transgenic intestinal organoids. Their integrated phenotype and pathway analysis links cell survival and motility to 4EBP1 and AKT phosphorylation.
The pre-mRNA splicing factor PRPF8 is a crucial component of the U5 snRNP. Using quantitative proteomics, Malinová et al. show that assembly of the U5 snRNP is controlled by the HSP90/R2TP chaperones and that Retinitis pigmentosa–associated mutations in PRPF8 impair PRPF8 quality control and U5 snRNP chaperone-mediated assembly.
Although chromosome fragments lacking a centromere would be expected to show severe defects in their segregation during anaphase, they do exhibit poleward movement by an unclear mechanism. Karg et al. now show how microtubules and the chromokinesin Klp3a can work together to successfully segregate chromosome fragments to daughter nuclei.
The initial kinetochore (KT) encounter with a spindle microtubule (MT) is one of the rate-limiting steps in establishing proper KT–MT interaction during mitosis. This study reveals how multiple factors cooperate to facilitate the KT encounter with a spindle MT. In particular, it highlights the important roles of KT-derived MTs in this process.
Auckland et al. describe a previously overlooked step during chromosome congression that provides insight into how kinetochore maturation is linked to attachment load-bearing, microtubule occupancy, and spindle assembly checkpoint signaling.
Microtubule-associated proteins with arrays of TOG domains differentially regulate microtubule dynamics. Byrnes and Slep show that TOG arrays are polarized containing architecturally distinct TOG domains that bind either free or microtubule lattice-incorporated tubulin, which is essential for microtubule polymerization and mitotic spindle formation.
Centrioles are known to be essential for cilia assembly. However, their contribution has not been clearly defined. Serwas et al. show that centrioles degenerate early in C. elegans ciliogenesis. Ciliary structures are not completely formed at this time, indicating that cilia maturation does not depend on intact centrioles.
Eukaryotic cells use diverse cellular mechanisms to crawl through complex environments. Fritz-Laylin et al. define α-motility as a mode of migration associated with dynamic, actin-filled pseudopods and show that WASP and SCAR constitute an evolutionarily conserved genetic signature of α-motility.
Intermediate filaments (IFs) participate in directed cell migration, but how the IF network becomes polarized in motile cells is unclear. Leduc and Etienne-Manneville show that the turnover of IF mainly relies on actin-driven retrograde flow and microtubule-driven anterograde and retrograde transport. During cell migration, Cdc42-mediated polarity signaling inhibits dynein-dependent transport to promote the polarization of the IF network.
Intracellular cargoes such as the nucleus and chloroplast are transported along microtubules toward minus ends in plant cells, despite the fact that plants have lost the genes encoding cytoplasmic dynein, a major minus end–directed transporter in animals. Yamada et al. identify multiple kinesin-14 motor family members as the minus end–directed transporters in moss cells.
Ion-dependent channels and transporters have been identified in lysosomes, including the V-ATPase H+ pump and transient receptor potential mucolipin channels (TRPMLs), the principle Ca2+ release channels in the lysosome, but much less is understood about the roles of Na+ and K+ in lysosomal physiology. Wang et al. describe a voltage-sensitive, Ca2+-activated K+ current in the lysosome (LysoKVCa) and show that LysoKVCa regulates lysosomal membrane potential and refilling of lysosomal Ca2+ stores.
Mammalian ER exit sites (ERES) export a variety of cargo molecules, including oversized cargoes such as collagens. Maeda et al. report a direct interaction between TANGO1 and Sec16 at ERES, which is not only important for their correct localization but also critical for the organization of ERES.
The coat protein complex II (COPII) is essential for the secretion of large cargo, such as procollagen I (PC1), but evidence that COPII vesicles act as PC1 transport carriers from the ER was lacking. Using high-resolution microscopy and in vitro reconstituted vesicle budding assays, Gorur et al. show that COPII vesicles carry PC1.
UPR transducer BBF2H7 allows export of type II collagen in a cargo- and developmental stage–specific manner
The unfolded protein response (UPR) handles misfolded proteins that accumulate in the ER, but it is unclear when or why vertebrates utilize different UPR transducers. Ishikawa et al. find that UPR transducer use changes during development of the notochord in medaka fish according to the length of collagen synthesized, from ATF6 alone (for folding of short-chain collagen) to ATF6 plus BBF2H7 (for folding and export of long-chain collagen).
Rab2 regulates multiple membrane traffic processes, but how it is recruited to and activated on the target membrane remains unclear. Here, Yin et al. identify a conserved protein, GOP-1, that activates UNC-108/Rab2 to promote phagosome, endosome, and DCV maturation.
Caspase-2 appears to be activated by the PIDDosome, but the role of PIDD in this pathway remains controversial. Ando et al. demonstrate that caspase-2 can be activated by two distinct complexes: one in the nucleolus that comprises PIDD and the nucleolar phosphoprotein NPM1, and one in the cytoplasm that is PIDD independent. Therefore, the nucleolus is a novel site for caspase-2 activation that appears to be essential for caspase-2 function.
Changes in nutrient availability trigger massive rearrangements of the yeast plasma membrane proteome. This work shows that the arrestin-related protein Csr2/Art8 is regulated by glucose signaling at multiple levels, allowing control of hexose transporter ubiquitylation and endocytosis upon glucose depletion.
Retinal stem cells yield all retinal cell types, but their embryonic origin is elusive. Using a Zebrabow-based clonal analysis and in vivo lineage analyses, Tang et al. identify bipotent progenitors as the cell of origin of retinal stem cells.
Usher syndrome type 1 (USH1) causes combined hearing and sight defects, but USH1 protein function in the retina is unclear. Schietroma et al. use Xenopus to model the deficiency in two USH1 proteins—protocadherin-15 and cadherin-23—and identify crucial roles for these molecules in shaping the photoreceptor outer segment.