People & Ideas
Casanova and Winckler discuss Liu et al.’s recent finding that WDR91 coordinates Rab and phosphoinositide conversion during endosome maturation in neurons.
Gekara previews studies published in Nature and Human Molecular Genetics identifying the subcellular localization where DNA lesions activate the innate immune response.
Dasso discusses work from Beaven et al. on the regulation of Ncd in the meiotic spindle by 14-3-3 proteins.
In mammals, the histone H1 family includes five somatic replication-dependent (H1.1–H1.5) and two replication-independent (H1.10 and H1.0) subtypes. Izzo et al. analyze the contributions of all somatic H1 subtypes to the chromatin landscape during reprogramming in preimplantation embryo and primordial germ cell development.
14-3-3 interacts with the kinesin-14 Ncd and prevents it from binding microtubules. Aurora B provides a spatial cue that releases Ncd from 14-3-3 around chromosomes, allowing Ncd to selectively bind the spindle microtubules in the large volume of oocytes.
Altering phosphoinositide composition through deletion of efr3, a PI4 kinase scaffold, results in type V myosin-dependent cytokinetic ring sliding in Schizosaccharomyces pombe. Membrane-binding proteins contribute to ring anchoring to resist perpendicular forces and thereby promote medial cytokinesis.
Bicaudal D2 (BICD2) is an adaptor protein that recruits and activates dynein–dynactin onto Rab6 membrane vesicles. Huynh and Vale reconstitute Rab6 regulation of BICD2-mediated dynein transport in vitro and show that disease-associated mutations in BICD2 cause an increase in retrograde transport.
Kraft and Lackner demonstrate that mitochondria drive the assembly of a tether, which serves to stably anchor the organelle itself as well as dynein to the plasma membrane. Thus, mitochondria–plasma membrane tethering influences when and where dynein is anchored, adding to the growing list of interorganelle contact site functions.
Kourtidis et al. demonstrate that cadherin complexes at the zonula adherens recruit a diverse set of mRNAs to a junction-associated RISC, via PLEKHA7. In this way, PLEKHA7 regulates expression of critical regulators of epithelial homeostasis, such as JUN, MYC, and SOX2, through Ago2 and miRNA-mediated silencing.
In this study, the authors show that the MRTF–SRF transcriptional pathway modulates sustained plasma membrane blebbing and entotic cell-in-cell invasion via regulation of the expression of the ERM protein Ezrin.
DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress
The elevated CDK2 activity of oncogene-expressing cells induces DNA replication stress. Yang et al. show that the DNA repair protein RAD18 facilitates damage-tolerant DNA synthesis via the DNA polymerase κ in cells with aberrantly high CDK2 activity, suggesting an important new role for RAD18 in sustaining neoplastic cell survival.
GTSE1 regulates spindle microtubule dynamics to control Aurora B kinase and Kif4A chromokinesin on chromosome arms
Mitosis involves complex interactions of multiple pathways, some yet uncharacterized. Tipton et al. use bioinformatics to implicate GTSE1 in mitosis. Depletion of GTSE1 disrupts chromosome alignment and spindle pole integrity, in part because of hyperstabilization of spindle microtubules and depletion of Aurora B kinase and Kif4A chromokinesin on chromosome arms.
The role of the Cdk regulatory protein cyclin A2 and its dynamics in female meiosis are unclear. Zhang et al. show that, unlike in mitosis, cyclin A2 persists during metaphase of meiosis II (MII). Cyclin A2 regulates microtubule stability, allows normal MII spindle formation, and prevents merotelic attachments and lagging chromosomes at MII exit.
Yeast silencing factor Sir4 and a subset of nucleoporins form a complex distinct from nuclear pore complexes
Lapetina et al. identify a protein interaction network involved in the association of chromatin with the nuclear envelope. This network includes a telomere tether, a silencing factor, a SUMO E3 ligase, and an array of nucleoporins that together form a complex distinct from nuclear pore complexes.
Qu et al. present the first evidence that mDia1-mediated stabilization of dynamic microtubules (MTs) and induction of tubulin posttranslational modifications drive tau hyperphosphorylation and synaptotoxicity, providing a novel target for therapy and the first mechanistic explanation as to why a dynamic MT cytoskeleton must be maintained to prevent neurodegenerative disease.
End-binding proteins regulate the dynamics and function of microtubule plus ends by recruiting a plethora of diverse factors. Yang et al. show that EB1 and EB3 also affect microtubule minus ends by participating in their attachment to Golgi membranes. This function is important for cell polarity and migration.
Perilipins are abundant proteins on the surface of mammalian cytoplasmic lipid droplets that protect the organelle from adventitious lipolysis. Gao et al. report the discovery of a perilipin in yeast and show that it is important for droplet stability and biogenesis.
Interorganelle membrane contacts work in a networked fashion to allow exchange of metabolites throughout the cell. In yeast, mitochondria–vacuole contacts act redundantly with ER–mitochondria contacts. We show that the yeast mitochondrial protein Mcp1 binds the endosomal/vacuolar protein Vps13 to mediate the physiological function of vacuole–mitochondria contacts.
The role of fission and autophagy in mitochondrial proteostasis is unclear. Burman et al. report that Drp1-mediated mitochondrial fission limits the spread of PINK1-activated Parkin ubiquitination to restrain mitophagy near sites of regional damage and allow the selective removal of subdomains.
Toxins produced by Shigella bacteria undergo endosome-to-Golgi retrograde trafficking to evade degradation in the lysosome and reach the cytosol. Selyunin et al. performed a genome-wide siRNA screen and identify host factors required for the transport and toxicity of Shiga toxins.
Microautophagy is a mode of autophagy in which the lysosomal or vacuolar membrane invaginates and engulfs target components. Oku et al. show that, upon a diauxic shift, yeast microautophagy involves recruitment of ESCRT proteins to the vacuolar membrane, including clathrin-interacting Vps27, and uptake of lipid droplets by the vacuole.
Recycling of internalized membrane proteins back to the cell surface controls diverse cellular processes. MacDonald and Piper genetically dissect a recycling pathway in yeast to reveal a cohort of novel and conserved factors, including the Rag GTPases, which contribute to metabolic control by regulating surface recycling independently of TORC1 signaling.
Axonal lysosomes accumulate abnormally in Alzheimer’s disease brains. However, whether and how such lysosomes contribute to disease pathology has been unclear. Gowrishankar et al. show that the JIP3-dependent transport of axonal lysosomes negatively regulates amyloid precursor protein processing into amyloidogenic peptides.
Early-to-late endosome conversion involves switching of early endosomes Rab5 and PtdIns3P to late endosomes Rab7 and PtdIns(3,5)P2. Liu et al. identify WDR91 as a Rab7 effector that couples Rab switching with PtdIns3P down-regulation on endosomes and show that WDR91 is essential for neuronal development.
Fiuza et al. report that PICK1 localizes to clathrin-coated pits and makes direct, functional interactions with the endocytic adapter complex AP2 and dynamin. The PICK1–AP2 interaction is required for clustering AMPA receptors at endocytic sites and for consequent AMPA receptor endocytosis, defining PICK1 as a cargo-specific endocytic accessory protein.
Neural crest cells are both highly migratory and significant to vertebrate organogenesis. However, the signals that regulate neural crest cell migration remain unclear. In this study, we identify DAN as a novel factor that inhibits uncontrolled neural crest and metastatic melanoma invasion in a manner consistent with the inhibition of BMP signaling.
Cells can survive executioner caspase activation following transient apoptotic stimuli, a process called anastasis. Using whole-transcriptome RNA sequencing, Sun et al. show that anastasis is an active, two-stage program and characterize the cell behaviors and molecular signature involved in the process.
J. Yao et al. demonstrate that loss of MGP, a BMP inhibitor, causes abnormal hepatic differentiation in lungs. They find that interactions between endothelium and epithelium separate pulmonary from hepatic differentiation during development. Lack of MGP triggers hepatic differentiation in the pulmonary epithelium, as regulated by the endothelium.
Filopodia, actin-rich finger-like protrusions, contribute to many pathophysiological conditions. Jacquemet et al. developed FiloQuant, a versatile open-source tool to quantify filopodia imaged using different techniques, including intravital microscopy, and reveal enhanced filopodia dynamics during local breast cancer invasion.
Urbančič et al. developed an open-source platform called Filopodyan (filopodia dynamics analysis) in Fiji and R to measure fluorescence in filopodia at their tips and bases concurrently with their morphological and dynamic properties. This customizable tool therefore enables researchers to determine the relationship between protein localization and filopodium behavior.