Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain
the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in
Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles
and JavaScript.
In performing its multiple cellular functions, the cytoplasmic dynein motor is subject to complex regulation involving allosteric mechanisms within the dynein complex, as well as numerous extramolecular interactions controlling subcellular targeting and motor activity. Recent work has distinguished high- and low-load regulatory modes for cytoplasmic dynein, which, combined with a diversity of targeting mechanisms, accounts for a very broad range of functions.
Clathrin adaptor proteins are essential for clathrin-coated vesicle biogenesis, yet the mechanisms governing their recruitment and interactions remain incompletely defined. The clathrin adaptors Gga and AP-1 are now shown to be recruited sequentially to the trans-Golgi network in two waves of clathrin coat assembly, coupled by Pik1-mediated phosphatidylinositol-4-phosphate synthesis. These findings reveal mechanistic insights into the functional and regulatory relationships between these clathrin adaptors.
Endothelial–vascular smooth muscle cell communication has a critical role in cardiovascular homeostasis and the pathogenesis of atherosclerosis. A study now demonstrates extracellular-vesicle-mediated transfer of the atheroprotective microRNAs miR-143/145 between endothelial and vascular smooth muscle cells, providing compelling evidence that intercellular transport of miRNAs can influence a pathological process, namely atherosclerosis.
Tumour cells undergo oncogene-regulated metabolic reprogramming that maximizes survival and growth. However, little is known about metabolic interactions between tumour cells and their non-malignant neighbours in the stroma. Bone-marrow-derived stromal cells are now shown to provide cysteine, an essential nutrient that enables leukaemia cells to resist oxidative stress.
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.
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.
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.
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.
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.
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.
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.
