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    ON THE COVER
    Madin-Darby Canine Kidney cells undergoing branching morphogenesis, stained with phalloidin to show the actin cytoskeleton. A z-stack encompassing a region of the sample is displayed with the final image reflected along the y axis.
    Image © Fessenden et al., 2018.
    See page 1485.

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ISSN 0021-9525
EISSN 1540-8140
In this Issue

In Focus

Phosphorylation by Src causes FHL1 to move into the nucleus and converts it from a tumor suppressor to a tumor promoter.

People & Ideas

Balla investigates how phosphoinositides control trafficking and signaling.

In Memoriam

Spotlight

Gemble and Basto preview work from Aydogan et al. that shows a homeostatic role for Plk4 in the regulation of centriole growth rate.

Boczek and Alberti discuss work from Grousl et al. describing how the heat shock protein Hsp42 binds and sequesters misfolded proteins.

Branzei and Giannattasio preview work from Roy et al. about a new assay for protein interactions with nascent DNA at replication forks called SIRF.

Review

Liu and Tjian review how superresolution and live-cell imaging are providing new insights into transcription factor dynamics and genome organization.

Deneke and Di Talia review how the spatiotemporal coordination of cellular functions across large distances is controlled by chemical waves.

Report

Ogungbenro et al. use reverse genetics in human hTERT-RPE1 cells and zebrafish to demonstrate novel roles for the centriolar BRCA2 interactor, centrobin, in controlling primary cilium formation through a C-terminal tubulin- and CP110-interacting region.

Article

Centriole duplication is tightly regulated throughout the cell cycle to ensure one duplication event per centriole. McLamarrah et al. show that a stepwise pattern of Ana2 phosphorylation by Plk4 facilitates proper centriole duplication.

Centrioles are highly structured organelles of consistent size across cell types. Aydogan et al. show that, in early Drosophila embryos, Plk4 functions as a homeostatic clock, establishing an inverse relationship between growth rate and period to ensure that daughter centrioles grow to the correct size.

cAMP signaling regulates Schwann myelination by a mechanism that is not clearly understood. The authors provide in vitro and in vivo data showing that cAMP shuttles HDAC4 into the nucleus, where it forms a complex with NcoR1/HDAC3 to repress the expression of c-Jun, inducing Schwann cell differentiation and myelin development.

The facilitated aggregation of misfolded proteins is a proteostasis strategy important for cell function and viability, but the molecular mechanisms are poorly understood. Grousl et al. reveal how the intrinsically disordered domains of the small heat shock protein Hsp42 promote and control the aggregation of misfolded proteins during stress conditions in yeast.

Recent findings suggest that the unfolded protein response plays important roles in insulin maturation. Tsuchiya et al. demonstrate that constitutive activation of the IRE1α–XBP1 pathway maintains high expression of five protein disulfide isomerases, promoting the oxidative folding of proinsulin.

Niewidok et al. analyze the distribution and dynamics of RNA-binding proteins (RBPs) with single-molecule resolution in living neuronal cells, providing direct support for liquid droplet behavior of stress granules in living cells and revealing transient binding of RBPs in nanocores.

Despite their shared ability to regulate microtubule polymerization dynamics, kinesin-4 motors display dramatically different motility properties ranging from fast processive motility to no movement. Yue et al. demonstrate that for KIF7 and KIF27, altered chemomechanical coupling results in immotile behavior and slow processive movement, respectively.

Wang et al. unveil a new mechanism by which Src may function as an oncogene. Phosphorylation of FHL1 by Src triggers the translocation of FHL1 to the nucleus, where it regulates the activity of the transcription factor BCLAF1 to promote tumor cell growth and loses the ability to regulate cell adhesion and suppress growth.

Montani et al. reveal that de novo fatty acid synthesis by Schwann cells, mediated by fatty acid synthase, contributes fundamentally to driving myelination in the peripheral nervous system. They identify lipogenic activation of the PPARγ transcriptional network as a putatively involved functional mechanism.

N-terminal matrix-targeting signals (MTSs) are critical for mitochondrial protein import. Backes et al. identified additional internal MTS-like sequences scattered along the sequences of mitochondrial proteins. By binding to Tom70 on the mitochondrial surface, these sequences support the import process.

Mitochondrial stress induces PARL-mediated cleavage and cytosolic release of the mitochondrial phosphatase Pgam5. In the cytosol, Pgam5 interacts with the Wnt pathway component axin and dephosphorylates axin-bound β-catenin, thereby cell-intrinsically activating Wnt/β-catenin signaling to induce mitochondrial biogenesis.

MHCII is essential for dendritic cells to function as antigen presenting cells; however, inhibiting MHCII degradation impairs regulatory T cell generation by an unknown mechanism. Oh et al. now report that MHCII turnover is an important quality-control mechanism in maintaining homeostasis of the lipid raft and tetraspanin domains required for Treg cell differentiation.

Yurchenko et al. discover that the Ig-like receptor molecule SLAMF1 enhances production of type I interferon induced by Gram-negative bacteria through modulation of MyD88-independent TLR4 signaling. This makes SLAMF1 a potential target for controlling inflammatory responses against Gram-negative bacteria.

Mesenchymal stem cell (MSC) fate decision is strongly influenced by cell microenvironment. Guo et al. identify kindlin-2 as a key determinant of MSC lineage commitment and delineate a novel signaling pathway consisting of kindlin-2, RhoA, MLCK, AIP4, and YAP1/TAZ that senses mechanical cues of the cell microenvironment and controls MSC differentiation.

Sun et al. establish the importance of transmission of changes in β-integrin transmembrane domain (TMD) topology in physiological integrin affinity modulation and biological function. Introduction of a flexible kink in the β7 integrin TMD blocks talin-mediated agonist-induced α4β7 integrin activation and function in gut lymphoid tissue development.

The yeast cell wall is digested to allow cell fusion during sexual reproduction. How cells coordinate this process with cell–cell contact to prevent lysis is unclear. Merlini et al. show that the Ras GAP protein Gap1, which is recruited to sites of Ras-GTP, restricts Ras activity and protects cells from lysis due to premature fusion attempts.

How collective cell migration mediates tissue shape changes during the development of normal tissue or tumors is unclear. Fessenden et al. show that the formin Dia1 stabilizes adhesions of protruding MDCK cells during branching morphogenesis, permitting force generation against collagen and eventual tissue shape changes.

In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. The study of Laban et al. provides evidence that VASP is a major regulator of leukocyte recruitment and polarization and vascular repair after ischemia. Mechanistically, the study supports a novel role of VASP in chemokine receptor trafficking.

Tools

Roy et al. describe a novel assay to measure direct protein associations at active and stalled DNA replication forks, called in situ analysis of protein interactions at DNA replication forks. The EdU-chase, click-chemistry, and PLA-composite system is quantitative, sensitive, and effective, with single-cell resolution suitable for concomitant multiparameter analysis.

Conic et al. introduce a versatile antibody-based imaging approach to track endogenous nuclear factors in living cells. It allows efficient intracellular delivery of any fluorescent dye–conjugated antibody, or Fab fragment, into a variety of cell types. The dynamics of nuclear targets or posttranslational modifications can be monitored with high precision using confocal and super-resolution microscopy.

Correction

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