Research articles

Lrig1, a transmembrane glycoprotein, has previously been shown to inhibit ErbB signalling. Jensen and colleagues show that Lrig1 controls the size of the intestinal stem-cell niche by modulating the amplitude of ErbB signalling. Thus, ErbB activation acts in concert with Wnt, Notch and Bmpr inhibition, to modulate stem-cell proliferation in the crypt.

ER stress activates the unfolded protein response (UPR), which can ultimately result in apoptosis. Using a Drosophila model of ER stress, Ryoo and colleagues find that apoptosis is induced independently of the known UPR branches. They show that ER stress induces CDK5-mediated phosphorylation of MEKK1, which activates JNK and induces apoptosis.

Meiotic recombination involves the generation of double-strand breaks, that needs to be carefully controlled to avoid fetal aneuploidy. In worms and yeast, crossover numbers are constant regardless of the amount of double-strand breaks. Jasin and colleagues now show that such crossover homeostasis mechanisms exist at two stages in mammalian meiosis.

The SCF ubiquitin ligase subunit Fbxw7 is a tumour suppressor that is mutated in many cancers. Pagano and colleagues now show that in multiple myeloma, Fbxw7α instead functions as a pro-survival factor by activating the NF-κB pathway through the ubiquitin-mediated degradation of p100, an NF-κB pathway inhibitor.

Bullock and colleagues have reconstituted in vitro the microtubule-driven transport of RNAs to specific localizations in Drosophila melanogaster embryos. They show that a set of localized messenger nucleoproteins (mRNPs) exhibits a strong bias in motility towards microtubule minus ends, correlating with an increase in the binding of dynein components (when compared with non-localizing bidirectionally moving mRNPs). They also find that a single mRNA transcript can be found within motile mRNPs, both in vitro and in vivo.

Cellular senescence is partly caused by RB1/E2F-mediated repression of proliferation genes. Bischof and colleagues now demonstrate that RB1 interacts with the microRNA effector AGO2, and that AGO2 and the microRNA let-7 are needed for chromatin remodelling and repression of E2F-target loci.

Formation and fission of large membrane-bound carriers at the Golgi requires coordinated action by a myriad of proteins, including PI(4)KIIIβ and CtBP1-S/BARS. Corda and colleagues reveal that the scaffold protein 14-3-3γ bridges BARS to PI(4)KIIIβ, thus mechanistically linking carrier budding and tubulation with tubule fission.

GGA proteins and the AP-1 complex are clathrin adaptors that regulate trans-Golgi network (TGN)-to-endosome traffic. Payne and colleagues show that these adaptors are recruited to the TGN in sequential waves, and reveal that phosphatidylinositol-4-monophosphate (PtdIns(4)P) coordinates the temporal assembly of these adaptors.

Elledge and colleagues performed siRNA (short interfering RNA) screens in human cells to identify regulators of homologous recombination (HR), a mechanism for the repair of double-strand breaks in DNA. Validation of screen data reveals the susceptibility of HR siRNA screens to off-target effects but defines the heterogeneous ribonucloprotein RBMX as a regulator of HR.

Chronic lymphocytic leukaemia cells depend on glutathione to counteract their high reactive oxygen species (ROS) levels. However, their ability to synthesize this antioxidant is compromised by inefficient cystine uptake. Huang and colleagues now show that bone marrow stromal cells promote leukaemia cell survival by metabolizing cystine to cysteine and releasing it into the microenvironment to be taken up by leukaemia cells.

Population-based studies in the haematopoietic system have suggested that global transcriptional noise drives lineage choice, with transcriptome-wide reversible changes occurring in self-renewing populations. Enver and colleagues use single-cell analysis to show that multipotent cells undergo independent activation of a few individual regulators that can sometimes induce a transition to the committed state.

In budding yeast, polarized Cdc42 localization is supported in part by guanine nucleotide dissociation inhibitor (GDI)-mediated extraction from the plasma membrane. Li and colleagues now show that a lipid flippase complex containing Lem3 and Dnf1 or Dnf2 contributes to membrane lipid asymmetry to facilitate GDI-mediated extraction of Cdc42.

Spindle orientation depends on the tethering of microtubules to the cell cortex through LGN, NuMA and dynein/dynactin. Cheeseman and colleagues find that spindle-pole-associated Plk1 activity restricts polar dynein whereas chromosomal RanGTP negatively regulates LGN localization at the lateral cell cortex, thus identifying two differentially localized signals that modulate spindle positioning by acting on dynein-mediated forces.

Dimmeler and colleagues show that the atheroprotective transcription factor KLF2 activates expression of the microRNAs miR-143/145 in endothelial cells. miR-143/145 are subsequently enriched in secreted microvesicles and taken up by smooth muscle cells to elicit anti-atherogenic responses.

Verma and colleagues develop a mouse model to study the role of the NF-κB pathway in lung cancer. They show that depletion of IKK2, a kinase needed for NF-κB activation, inhibits the induction of Timp1. This suppresses the Timp-1-mediated activation of Erk, resulting in decreased tumour-cell proliferation and prolonged survival.

The formation of a bipolar spindle is critical for accurate segregation of the genome. Maiato and colleagues now demonstrate that CLASPs (cytoplasmic linker associated proteins) prevent spindle multipolarity in a manner independent of end-on kinetochore–microtubule attachments. They propose that CENP-E-mediated traction forces are balanced by CLASP-mediated recruitment of ninein to centriolar satellites.

Cyclin B is targeted for proteasome-mediated degradation by the E3 ligase APC/C, which is thought to generate polyubiquitin chains for the degradation of mitotic substrates. King and colleagues now demonstrate in Xenopus laevis extracts that multiple monoubiquitylation events are sufficient to target cyclin B1 for degradation.

Oxygen levels regulate the stability of the transcription factor HIF-1 through the action of prolyl hydroxylases and the VHL ubiquitin ligase. Sharp and colleagues now identify a protein complex in which the Ajuba LIM-domain protein LIMD1 brings together prolyl hydroxylases and VHL to ensure efficient degradation of HIF-1.

Asymmetric Notch signalling is important in many developmental contexts, including the division of fly sensory organ precursor (SOP) cells. Here, Notch is inactivated by Numb in the resulting pIIb daughter cell while remaining active in pIIa to direct cell fate. Using live imaging, Schweisguth and colleagues reveal that Numb and Sanpodo act together, modulating Notch trafficking to deplete it on the pIIb side of the SOP cytokinetic furrow.

Damaged mitochondria can be removed by mitophagy, but how this organelle is recognized by the autophagy machinery is unclear. Chen and colleagues show that FUNDC1, an integral mitochondrial outer membrane protein, interacts with light chain 3 (LC3) and is essential for hypoxia-induced mitophagy.