Research articles

In mammalian cells, long-range vesicular transport is thought to occur via microtubule tracks. However, Schuh reports the existence of an actin-based pathway for long-range trafficking in mouse oocytes by showing that Rab11a-positive vesicles are decorated with actin-nucleating formin proteins. She finds that these proteins assemble actin networks that guide vesicles to the cell surface.

PAR polarity proteins are asymmetrically localized at the cortex of Caenorhabditis elegans zygotes. Seydoux and colleagues show that aPKC-mediated phosphorylation of PAR-2, which inhibits recruitment of PAR-2 to the cortex, is directly inhibited by microtubules emanating from the sperm-donated centrosomes. This protection allows PAR-2, and subsequently the PAR-1 kinase to access the cortex nearby the sperm, thus defining the posterior of the embryo. PAR-1 in turn phosphorylates PAR-3 to induce dissociation of PAR-3–aPKC from the posterior.

Spector and colleagues demonstrate that transcriptional activation after mitosis occurs with much faster kinetics than in interphase. Increased acetylation of lysine 5 on histone H4 is maintained during mitosis to recruit bromodomain protein 4, which then facilitates chromatin decompaction for transcriptional reactivation.

The ubiquitin–proteasome system clears misfolded proteins to maintain cellular homeostasis. Mayor and colleagues identify the ubiquitin ligase Hul5 as a critical component of the heat-shock response and show that it selectively targets misfolded cytosolic proteins for degradation.

In yeast, polarized localization of Cdc42 is essential for budding and mating, but how polarity is attained has been elusive. Grinstein and colleagues show that phosphatidylserine accumulates in a polar fashion in yeast, and is required for the proper localization of Cdc42.

In humans, mutations in the DNA-damage-response modulator MCPH1 are associated with defective neural development. Wang and colleagues show that mutations in mouse MCPH1 result in microcephaly through the delocalization of Chk1 from centrosomes, causing the uncoupling of mitosis and centrosome duplication, and resulting in spindle misorientation and a switch in the fate of neural stem cell daughters.

In the TGFβ pathway, receptor-activated SMADs (R-SMADs) associate with SMAD4 to regulate transcription. Piccolo and colleagues reveal that the deubiquitylase USP15 is required for TGFβ responses by reversing R-SMAD ubiquitylation and thereby promoting the retention of the SMAD complex at promoters.

Non-enveloped viruses such as SV40 are transported from the extracellular space into the host cell nucleus through a pathway involving endocytosis, trafficking to the endoplasmic reticulum (ER) lumen, transport across the ER membrane to the cytoplasm, and subsequent nuclear import. Helenius and colleagues provide insight into how SV40 escapes from the ER by showing that viral proteins interact with components of the host ER-associated degradation machinery (ERAD). These interactions are crucial for translocation of SV40 into the cytoplasm and infectivity.

Ivaska and colleagues identify SHARPIN as an inhibitor of integrin activity in an RNAi screen for integrin regulators. They show that SHARPIN acts by binding to the cytoplasmic domain of integrin α-subunits and reduces the recruitment of talin and kindlin to the β-subunits.

The spindle assembly checkpoint halts cell-cycle progression in the presence of unattached kinetochores by preventing activation of APC/C. Pines and colleagues find that APC15 has a critical role in regulating APC/C activation by promoting release of the inhibitory MCC complex from APC/C once the spindle assembly checkpoint is satisfied.

ATP production by mitochondria requires the efficient flow of protons through the F₁F_O ATP-synthase complex. Jonas and colleagues show that Bcl-xL interacts with the F₁F_O complex in the mitochondrial matrix and increases the efficiency of this enzyme by decreasing proton leak.

Cell polarity is critically important for organogenesis. Using a series of RNA-interference-based screens, Göbel and colleagues reveal the role of the glycosphingolipid glucosylceramide (GlcCer) in determining apicobasal polarity and maintaining the organization of the intestinal lumen in the developing worm.

Notch and VEGF signalling controls the specification of endothelial cells to tip and stalk cells during angiogenesis sprouting. Alitalo and colleagues show that macrophage-derived VEGF-C activates VEGFR2 to contribute to the conversion of endothelial cells from a tip- to a stalk-cell fate when two sprouts fuse to ensure vessel growth and branching.

Doxsey and colleagues report that midbodies accumulate in stem cells, including induced pluripotent stem cells and potential cancer-initiating cells. Loss of midbodies accompanies stem-cell differentiation and is mediated through binding of the autophagy receptor NBR1 to the midbody protein CEP55. Downregulation of NBR1 is associated with enrichment of midbodies, enhanced reprogramming and increased tumorigenicity in cancer cells.

Overlapping antiparallel microtubules are important in cellular structures such as the mitotic spindle. Diez and colleagues use an in vitro system and mathematical modelling to show that the formation of stable overlaps involves a motor such as kinesin-14, which slides microtubules apart, and a passive microtubule crosslinker, Ase1, which accumulates at microtubule overlapping regions and slows microtubule sliding to prevent their separation.

The microtubules that attach kinetochores to chromosomes (K-fibres) are stabilized in prometaphase to allow for accurate chromosome segregation. Kapoor and colleagues find that the B56-PP2A phosphatase stabilizes K-fibres potentially by counteracting the phosphorylation of kinetochore substrates that is mediated by Aurora B and Plk1.

Mammalian oocyte maturation involves two asymmetric meiotic divisions that require the positioning of the meiotic spindle near the cortical area from which the extrusion of the polar bodies occurs. Li and colleagues show that the nucleating activity of the Arp2/3 complex, localized at the cortical actin cap, induces actin-filament flow away from the complex, creating a cytoplasmic streaming that pushes the spindle towards the cortex.

Franzoso and colleagues show that NF-κB protects cells from nutrient-starvation-induced necrosis by upregulating mitochondrial respiration through increased p53-dependent expression of the SCO2 enzyme. Conversely, inhibition of NF-κB results in increased aerobic glycolysis, known as the Warburg effect, thus promoting oncogenic transformation, and affects metabolic adaptation during tumorigenesis in vivo.

The LIN-5/NuMA pathway is needed to correctly position the mitotic spindle for asymmetric division. Now van den Heuvel and colleagues find that polarity kinase aPKC–PKC-3 phosphorylates LIN-5 to direct the localization of the spindle in the early embryos of Caenorhabditis elegans.

Drosophila L(3)mbt mutant brains are shown to develop brain tumours owing to derepression of the target genes of the Salvador–Warts–Hippo pathway, resulting in overproliferation of neuroepithelial cells in the optic lobes. L(3)mbt is found to act in this process by binding to insulator elements at the promoters of these target genes.