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Novel perspectives emerge from a recent conference on the origins of eukaryotic cells, which covered phylogenetics, population genetics and evolutionary consequences of energy requirements and host–pathogen interactions.
Dynamic changes in the chromatin of adult stem cells are required to establish the gene expression profiles associated with stem cell self-renewal and differentiation. A complex genetic network of chromatin remodellers and epigenetic factors orchestrate these genome-wide changes in human epidermal stem cells.
Exosomes have a growing inventory of functions, but the mechanism of protein sorting into exosomes has been unclear. Now, a signal sequence first described in viral budding provides just such a cargo sorting mechanism, revealing closer-than-expected parallelism between exosome biogenesis and the ESCRT-dependent endolysosomal pathway.
The transforming growth factor (TGF-β) pathway is regulated by ubiquitin-mediated proteolysis at different levels. Two studies now identify deubiquitinating enzymes (DUBs) for the TGF-β type I receptor. Both ubiquitin-specific peptidase-4 (USP4) and -15 (USP15) extend the life of activated receptors against the negative pressure of receptor-ubiquitinating complexes, but through distinct modes of action.
Reik and colleagues show that deletion of the large intergenic non-coding RNA H19 leads to unlimited placenta growth. They find that the H19 RNA contains a microRNA that targets the insulin-like growth factor receptor IGF-1R, and demonstrate that the RNA-binding protein HuR prevents miR-675 excision from H19 until miR-675 activity is required to halt placenta growth.
RAB-11-positive recycling endosomes participate in the establishment and maintenance of epithelial polarity. Zerial and colleagues carry out an in vivo image-based RNAi screen for factors that regulate recycling endosome positioning in Caenorhabditis elegans. They identify, among other candidates, PAR-5 as a key determinant of recycling endosome positioning and, thus, apicobasal polarity.
Exosomes are increasingly recognized as key intermediaries of intercellular communication, yet the mechanisms governing their biogenesis remain unclear. Zimmermann, David and colleagues report that interactions between the transmembrane protein syndecan, its associated protein syntenin and the ESCRT adaptor ALIX are necessary for exosome formation, supporting a role for the ESCRT machinery in this process.
Wu and colleagues delineate an mTORC2-dependent cell migration pathway. They show that stimulation of the Gα12 protein subunit induces the ARAF/ERK-mediated expression of the RFFL E3 ubiquitin ligase. RFFL, in turn, targets the inhibitory PRR5L subunit of the mTORC2 complex for ubiquitylation and degradation, enabling mTORC2 to phosphorylate PKC-δ and promote cell migration.
Ciliogenesis requires the removal of CP110 from the mother centriole, and is influenced by actin dynamics. Zhu and colleagues now show that the microRNA miR-129-3p controls primary cilia formation in vertebrates by downregulating CP110 and targeting multiple actin regulators to suppress actin dynamics.
The endoplasmic reticulum (ER) forms an intricate network of interconnected tubules. Sey1 is known to govern tubule formation, but the proteins that counteract tubule fusion remained unclear. Chen, Novick and Ferro-Novick propose that Lnp1 antagonizes the activity of Sey1 to modulate ER network formation.
Ten Dijke and colleagues identify USP4 as a deubiquitylating enzyme (DUB) for the TGF-β receptor I in a screen for ubiquitin-specific proteases affecting TGF-β signalling. USP4, present in a complex with other DUBs, is regulated by AKT-mediated phosphorylation and is required for TGF-β-induced breast cancer cell migration and metastasis.
Li and colleagues report that c-Abl regulates the responses downstream of bone morphogenetic protein (BMP) that direct proliferation or senescence in osteoblasts. They show that phosphorylation of the BMP receptor BMPR1A by c-Abl promotes downstream Smad-mediated responses and osteoblast expansion, whereas in the absence of c-Abl, BMP activates Erk signalling, leading to p16INK4a-induced senescence.
In fission yeast, the septum initiation network (SIN) regulates septation at the end of mitosis. Hagan and colleagues now reveal a further role for the SIN kinase Sid2 that is independent of other known SIN components, in the control of entry into mitosis through phosphorylation of the NIMA kinase Fin1.
The kinase MPS1 is a conserved and essential component of the spindle assembly checkpoint (SAC), but its relevant substrate in this context has remained uncertain. Watanabe and colleagues now show that, in fission yeast and human cells, MPS1 (Mph1 in fission yeast) phosphorylates the kinetochore protein KNL1 (Spc7), leading to kinetochore recruitment of BUB1, an event required for SAC activation.
Watt and colleagues carried out an RNAi screen to identify epigenetic modifiers involved in the control of epidermal differentiation. They delineate a network of genetic interactions using a Bayesian mixture model approach, and uncover two complexes of modifiers that differentially affect self-renewal and differentiation of epidermal stem cells.
Pepperkok, Simpson and colleagues performed genome-wide RNAi screens in human cells to uncover regulators of the secretory pathway. They also identify protein networks with previously unappreciated roles in secretory pathway regulation.
