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bioRxiv2018

Translational control through differential ribosome pausing during amino acid limitation in mammalian cells

Limitation for amino acids is thought to regulate translation in mammalian cells primarily by signaling through the kinases mTORC1 and GCN2. We find that limitation for the amino acid arginine causes a selective loss of tRNA charging, which regulates translation through ribosome pausing at two of six arginine codons. Surprisingly, limitation for leucine, an essential and abundant amino acid in protein, results in little or no ribosome pausing. Chemical and genetic perturbation of mTORC1 and GCN2 signaling revealed that their robust response to leucine limitation prevents ribosome pausing, while an insufficient response to arginine limitation led to loss of arginine tRNA charging and ribosome pausing. Codon-specific ribosome pausing decreased protein production and triggered premature ribosome termination without significantly reducing mRNA levels. Together, our results suggest that amino acids which are not optimally sensed by the mTORC1 and GCN2 pathways still regulate translation through an evolutionarily conserved mechanism based on codon-specific ribosome pausing.

cell biology↗

bioRxiv2018

Clathrin plaques form mechanotransducing platforms

Large flat clathrin plaques are stable features of the plasma membrane associated with sites of strong adhesion suggesting that they could also play a role in force transduction. Here, we analyzed how clathrin plaques interact with the cytoskeleton and how they respond to mechanical cues in skeletal muscle myotubes. We show that branched actin networks surrounding clathrin plaques are directly regulated by dynamin 2, anchor intermediate filaments and sequester YAP at the plasma membrane. Dynamin 2, clathrin and desmin intermediate filaments are all required for basal YAP nucleocytoplasmic distribution and efficient nuclear translocation in response to mechanical stimuli. Dynamin 2 mutations that are responsible for centronuclear myopathy in humans disorganize the desmin network and deregulate YAP signaling both in vitro and in vivo. Thus, clathrin plaques and associated dynamin 2 are defined here as a new sensor conveying mechanical cues and integrate cell signaling with cytoskeletal regulation.

cell biology↗

bioRxiv2018

Metastable XBP1u transmembrane domain mediates insertion into the ER membrane and intramembrane proteolysis by the signal peptide peptidase

Unspliced XBP1 mRNA encodes XBP1u, the transcriptionally inert variant of the unfolded protein response (UPR) transcription factor XBP1s. XBP1u targets its mRNA-ribosome-nascent-chain-complex to the endoplasmic reticulum (ER) to facilitate UPR activation and prevents overactivation. Yet, its membrane association is controversial. Here, we use cell-free translocation and cellular assays to define a moderately hydrophobic stretch in XBP1u that is sufficient to mediate insertion into the ER membrane. Mutagenesis of this transmembrane (TM) region reveals residues that facilitate XBP1u turnover by an ER-associated degradation route that is dependent on signal peptide peptidase (SPP). Furthermore, the impact of these mutations on TM helix dynamics was assessed by residue-specific amide exchange kinetics, evaluated by a semi-automated algorithm. Based on our results, we suggest that SPP-catalyzed intramembrane proteolysis of TM helices is not only determined by their conformational flexibility, but also by side chain interactions near the scissile peptide bond with the enzymes active site.

cell biology↗

bioRxiv2018

Relief of the Dma1-mediated checkpoint requires Dma1 autoubiquitination and dynamic localization

Chromosome segregation and cell division are coupled to prevent aneuploidy and cell death. In the fission yeast Schizosaccharomyces pombe, the septation initiation network (SIN) promotes cytokinesis, but upon mitotic checkpoint activation, the SIN is actively inhibited to prevent cytokinesis from occurring before chromosomes have safely segregated. SIN inhibition during the mitotic checkpoint is mediated by the E3 ubiquitin ligase Dma1. Dma1 binds to the CK1-phosphorylated SIN scaffold protein, Sid4, at the SPB, and ubiquitinates it. Sid4 ubiquitination antagonizes the SPB localization of the Polo-like kinase Plo1, the major SIN activator, so that SIN signaling is delayed. How this checkpoint is silenced once spindle defects are resolved has not been clear. Here we establish that Dma1 transiently leaves SPBs during anaphase B due to extensive auto-ubiquitination. The SIN is required for Dma1 to return to SPBs later in anaphase. Blocking Dma1 removal from SPBs by permanently tethering it to Sid4 prevents SIN activation and cytokinesis. Therefore, controlling Dma1s SPB dynamics in anaphase is an essential step in S. pombe cell division and the silencing of the Dma1-dependent mitotic checkpoint.

cell biology↗

bioRxiv2018

Microtubule dynamics is required for rapid coiling of haptonemata in haptophyte algae

A haptonema is an elongated microtubule-based motile organelle uniquely present in haptophytes. The most notable and rapid movement of a haptonema is \"coiling\", which occurs within a few milliseconds following mechanical stimulation in an unknown motor-independent mechanism. Here, we analyzed the coiling process in detail by high-speed filming and showed that haptonema coiling was initiated by left-handed twisting of the haptonema, followed by writhing to form a helix from the distal tip. On recovery from a mechanical stimulus, the helix slowly uncoiled from the proximal region. Electron microscopy showed that the seven microtubules in a haptonema were arranged mostly in parallel but that one of the microtubules often wound around the others in the extended state. The persistence lengths calculated from the curvature of the haptonematal microtubules indicated their unusual flexibility. A microtubule stabilizer, paclitaxel, inhibited coiling and induced right-handed twisting of the haptonema in the absence of Ca2+, suggesting changes in the microtubule surface lattice. Addition of Ca2+ caused bend propagation toward the proximal region. These results indicate that switching microtubule conformation with the aid of Ca2+-binding microtubule-associated proteins is responsible for rapid haptonematal coiling.\n\nSummary StatementMicroscopy observations and pharmacological experiments revealed that the rapid coiling of a non-motor microtubule-based motile organelle, the haptonema, is explained by conformational changes of microtubules, including twisting and writhing.

cell biology↗

bioRxiv2018

The RZZ complex facilitates Mad1 binding to Bub1 ensuring efficient checkpoint signaling

Introductory paragraphThe recruitment of Mad1 to unattached kinetochores is essential for generating a \"wait anaphase\" signal during mitosis yet Mad1 localization is poorly understood in mammalian cells. In yeast the Bub1 checkpoint protein is the sole Mad1 receptor but in mammalian cells the Rod-ZW10-Zwilch (RZZ) complex is also required for Mad1 kinetochore localization. The exact function of the two mammalian Mad1 receptors and whether there is any interplay between them is unclear. Here we use CRISPR genome editing to generate RNAi sensitized human cell lines revealing a strong requirement for both Rod and Bub1 in checkpoint signaling. We show that the RZZ complex facilitates Mad1 binding to Bub1 and that a region of Bub1 overlapping the Mad1 binding site stimulates RZZ kinetochore recruitment. The requirement for RZZ in the checkpoint, but not Bub1, can be bypassed by tethering Mad1 to kinetochores or by increasing the strength of the Bub1-Mad1 interaction. Our data support a model in which the primary role of RZZ is to localize Mad1 at kinetochores allowing for the efficient checkpoint generating Mad1-Bub1 interaction. As such, the core checkpoint principle is conserved from yeast to man.

cell biology↗

bioRxiv2018

A proteome-wide screen reveals widespread roles for the phosphatase Cdc14 in the Candida albicans cell cycle

The chromosome complement of the human fungal pathogen Candida albicans is unusually unstable, suggesting that process of nuclear division is error prone. The Cdc14 phosphatase plays a key role in organising the intricate choreography of mitosis and cell division. In order to understand the role of Cdc14 in C. albicans we used quantitative proteomics to identify proteins that physically interact with CaCdc14. To distinguish genuine Cdc14-interactors from proteins that bound non-specifically bound to the affinity matrix we used an orthogonal approach of a substrate trapping mutant combined with mass spectrometry analysis using stable isotope labelling in cell culture (SILAC). The results identified 126 proteins that interact with Cdc14 of which 80% are novel. In this set, 53 proteins play known roles in the cell regulating the attachment of the mitotic spindle to kinetochores, mitotic exit, cytokinesis, licensing of DNA replication by re-activating pre-replication complexes, and DNA repair. Five Cdc14-interacting proteins with previously unknown functions localized to the Spindle Pole Bodies (SPBs). Intriguingly, 83 proteins that only interacted with Cdc14 in yeast were significantly enriched in components of the ergosterol biosynthesis pathway targeted by azole anti-fungal drugs. Thus we have greatly expanded the set of known substrates of this key cell cycle regulator in C. albicans.\n\nAuthor summaryCandida albicans is an important fungal pathogen causing life-threatening bloodstream infections in humans, as well as debilitating mucosal infections. Here we used Mass Spectroscopy to identify proteins that physically interacted with an enzyme called Cdc14. By removing phosphate groups from proteins, and thus regulating their function, this enzyme orchestrates the intricate molecular mechanisms of nuclear division to ensure that each daughter cell receives a full complement of chromosomes. C. albicans is unusual in the way that changes in chromosome number and composition are much more common than in other organisms. This suggests that the process of nuclear division may be more error prone in C. albicans. Our work identified 126 proteins that physically associate with Cdc14 and are thus potential substrates, including 53 proteins that we know are involved in many cell cycle processes that are necessary for nuclear and cell division. Thus, we have laid the ground work to study how changes in chromosomal composition may arise due to errors in nuclear division in this important pathogen. Unexpectedly, we found that Cdc14 may also act on proteins involved in the synthesis of ergosterol, a key lipid in the cell membrane. Azoles, a major class of antifungal drugs, inhibit the synthesis of ergosterol, so Cdc14 may also be involved in the action of azoles and thus one possible way in which drug resistance arises.

cell biology↗

bioRxiv2018

Genome-Scale CRISPR Screening Identifies Novel Human Pluripotent Gene Networks

Human pluripotent stem cells (hPSCs) generate a wide variety of disease-relevant cells that can be used to improve the translation of preclinical research. Despite the potential of hPSCs, their use for genetic screening has been limited because of technical challenges. We developed a renewable Cas9/sgRNA-hPSC library where loss-of-function mutations can be induced at will. Our inducible-mutant hPSC library can be used for an unlimited number of genome-wide screens. We screened for novel genes involved in 3 of the fundamental properties of hPSCs: Their ability to self-renew/survive, their capacity to differentiate into somatic cells, and their inability to survive as single-cell clones. We identified a plethora of novel genes with unidentified roles in hPSCs. These results are available as a resource for the community to increase the understanding of both human development and genetics. In the future, our stem cell library approach will be a powerful tool to identify disease-modifying genes.\n\nVISUAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC=\"FIGDIR/small/323436_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (48K):\norg.highwire.dtl.DTLVardef@5101e4org.highwire.dtl.DTLVardef@5321f2org.highwire.dtl.DTLVardef@1d9c94corg.highwire.dtl.DTLVardef@12ebd53_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2018

Localization and protein-protein interaction of protein kinase CK2 suggest a chaperone-like activity is integral to its function in M. oryzae.

Magnaporthe oryzae (Mo) is a model pathogen causing rice blast resulting in yield and economic losses world-wide. CK2 is a constitutively active, serine/threonine kinase in eukaryotes, having a wide array of known substrates and involved in many cellular processes. We investigated the localization and role of MoCK2 during growth and infection. BLAST search for MoCK2 components and targeted deletion of subunits was combined with protein-GFP fusions to investigate localization. We found one CKa and two CKb subunits of the CK2 holoenzyme. Deletion of the catalytic subunit CKa was not possible and might indicate that such deletions are lethal. The CKb subunits could be deleted but they were both necessary for normal growth and pathogenicity. Localization studies showed that the CK2 holoenzyme needed to be intact for normal localization at septal pores and at appressorium penetration pores. Nuclear localization of CKa was however not dependent on the intact CK2 holoenzyme. In appressoria, CK2 formed a large ring perpendicular to the penetration pore and the ring formation was dependent on the presence of all CK2 subunits. The effects on growth and pathogenicity of deletion of the b subunits combined with the localization indicate that CK2 can have important regulatory functions not only in the nucleus/nucleolus but also at fungal specific structures as septa and appressorial pores.

cell biology↗

bioRxiv2018

Fyn Is Involved In Erythropoietin Signaling Pathway And Interfaces Oxidation To Regulate Erythropoiesis

Erythropoiesis is a complex multistep process responsible of the production of circulating mature erythrocytes and involved the production of reactive oxygen species (ROS) during erythroid differentiation. Here, we document that Fyn, a Src-family-kinase, participates in erythropoietin (EPO) signaling pathway, by the reducing extent of Tyr-phosphorylation of EPO-R and by decreasing STAT5 activity. The importance of Fyn in EPO cascade is also supported by the increased sensitivity of Fyn-/- mice to stress erythropoiesis. Fyn -/- mouse erythroblasts adapt to the induced stress by the activation of the redox-related-transcription-factor Nrf2. However, the absence of the Nrf2 physiologic repressor Fyn resulted in the persistent activation of Nrf2 and accumulation of non-functional proteins. This is paralleled by ROS induced over-activation of Jak2-Akt-mTOR pathway and repression of autophagy and perturbation of lysosomal-clearance during Fyn -/- reticulocyte maturation. Treatment with Rapamycin, a mTOR inhibitor and autophagy activator, ameliorates Fyn-/- mouse baseline erythropoiesis and restored the erythropoietic response to phenylhydrazine. Taken together these findings have enabled to identify the novel multimodal action of Fyn in the developmental program of erythropoiesis.

cell biology↗

bioRxiv2018

Neuronal Modulation of Brown Adipose Activity Through Perturbation of White Adipocyte Lipogenesis

White adipose tissue (WAT) secretes factors to communicate with other metabolic organs to maintain energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) causes expansion of sympathetic neurons within white adipose tissue (WAT) and the appearance of \"beige\" adipocytes. Here we report evidence that white adipocyte DNL activity is also coupled to neuronal regulation and thermogenesis in brown adipose tissue (BAT). Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. In contrast, selective ablation of FASN in brown adipocytes of mice (iUCP1FASNKO) failed to modulate sympathetic innervation and the thermogenic program in BAT. Surprisingly, DNL in brown adipocytes was also dispensable in maintaining euthermia when UCP1FASNKO mice were cold-exposed. These results indicate that DNL in white adipocytes influences long distance signaling to BAT, which can modify BAT sympathetic innervation and expression of genes involved in thermogenesis.

cell biology↗

bioRxiv2018

Cellular Crowding Influences Extrusion and Proliferation to Facilitate Epithelial Tissue Repair

Epithelial wound healing requires a complex orchestration of cellular rearrangements and movements to restore tissue architecture and function after injury. While it is well-known that mechanical forces can affect tissue morphogenesis and patterning, how the biophysical cues generated after injury influence cellular behaviors during tissue repair is not well understood. Using time-lapsed confocal imaging of epithelial tissues in living zebrafish larvae, we provide evidence that localized increases in cellular crowding during wound closure promote the extrusion of non-apoptotic cells via mechanically regulated stretch-activated ion channels (SACs). Directed cell migration toward the injury site promoted the rapid changes in cell number and generated shifts in tension at cellular interfaces over long spatial distances. Perturbation of SAC activity resulted in failed extrusion and increased proliferation in crowded areas of the tissue. Together, we conclude that localized cell number plays a key role in dictating cellular behaviors that facilitate wound closure and tissue repair.

cell biology↗

bioRxiv2018

Dorsal Ruffles Enhance Activation of Akt by Growth Factors

In fibroblasts, platelet-derived growth factor (PDGF) stimulates macropinocytosis and PI 3-kinase (PI3K)-dependent phosphorylation of Akt, leading to activation of mTORC1, a protein complex controlling metabolism and cell growth. PIP3, the phosphoinositide product of PI3K that activates Akt, is frequently concentrated within the macropinocytic cups of growth factor-stimulated cells, which suggests that cup structure enhances phosphorylation of Akt by facilitating PI3K activity. However, inhibitors of the cytoskeleton which block cup formation do not reduce Akt phosphorylation in response to high concentrations of PDGF. Because the dynamics of Akt phosphorylation after stimulation by PDGF can differ from those that follow stimulation with epidermal growth factor (EGF), we analyzed the contributions of the actin and microtubule cytoskeleton to activation of Akt by these two growth factors. Actin-rich, circular dorsal ruffles (CDR), analogous to macropinocytic cups, appeared within several minutes of adding EGF or PDGF and often closed to form macropinosomes. Nocodazole, an inhibitor of microtubule polymerization, blocked both PDGF- and EGF-induced CDR formation, and inhibited phosphorylation of Akt in response to EGF but not PDGF. At concentrations that saturate their cognate receptors, EGF stimulated lower maximal levels of Akt phosphorylation than did PDGF. We hypothesized that weak signals elicited by EGF receptors require cytoskeleton-dependent amplification of PI3K for maximal phosphorylation of Akt. In both PDGF- and EGF-stimulated cells, quantitative immunofluorescence showed increased Akt phosphorylation in cells containing CDR, with PIP3 and Akt concentrated in CDR and ruffles. Stimulation with low concentrations of PDGF elicited lower levels of Akt phosphorylation, which, like responses to EGF, were inhibited by nocodazole. These results indicate that when receptor signaling generates low levels of PI3K activity, CDR facilitate local amplification of PI3K, PIP3 synthesis and phosphorylation of Akt.

cell biology↗

bioRxiv2018

The Kinesin-1 binding domain of Ensconsin/MAP7 promotes Kinesin-1 activation in vivo

Centrosome separation in Drosophila larval neuroblasts and asymmetric transport of embryonic determinants in oocytes are both microtubule-dependent processes that require Kinesin-1 activation by Ensconsin/microtubule-associated protein 7 (MAP7). However, the molecular mechanism used by Ensconsin to activate Kinesin-1 remains elusive. Ensconsin/ MAP7 contains an N-terminal microtubule-binding domain (MBD) and a C-terminal Kinesin-binding domain (KBD). Using rescue experiments in live flies, we show that KBD expression alone is sufficient to fully rescue Ensconsin-dependent centrosome separation defects, but not the fast oocyte streaming and the localization patterns of Staufen and Gurken proteins. Interestingly, we show here for the first time that KBD binds and stimulates Kinesin-1 binding to Mts in vivo and in vitro. We propose that the KBD/Kinesin-1 motor represents a minimal activation module that stimulates Kinesin-1 binding to Mts. Addition of the MBD, present in the full length Ensconsin allows this activation to occur directly on the Mt. Our data also suggest that in a very large cell with a complex microtubule network, but not in smaller cells, this dual activation by Ensconsin is essential for optimal Kinesin-1 targeting to the microtubule cytoskeleton.

cell biology↗

bioRxiv2018

The Influence of PTH 1-34 on the Osteogenic Characteristics of Adipose and Bone Marrow Derived Stem Cells from Juvenile and Ovarectomized Rats

Background: Mesenchymal Stem Cells (MSCs) are of growing interest in terms of bone regeneration; the majority of preclinical trials utilise bone marrow derived stem cells (bMSCs), though this is not without isolation and expansion difficulties\n\nObjective: We compare the characteristics of bone marrow and adipose derived cells from juvenile, adult and ovarectomized rats; also assessing the effect of hPTH 1-34, on their osteogenic potential.\n\nMethods: cells were isolated from the adipose and bone marrow of juvenile, adult and previously ovarectomized wistar rats. Cells were characterised with flowcytometery, proliferation assays, osteogenic and adipogenic differentiation, and migration to SDF-1. Experiments were repeated with and without co-culturing with 50nMol of intermittent PTH 1-34.\n\nResults: The juvenile and adult MSCs demonstrated significantly increased differentiation into bone and fat and superior migration towards SDF-1 than ovarectomized groups, this was the case for adipose and bone marrow derived cells equally. PTH increased parameters of osteogenic differentiation and migration to SDF-1, this was significant for all cell types, though had the most significant effect on cells derived from OVX animals. Bone marrow derived cells from all groups, showed increased mineralisation and migration to SDF-1 compared to adipose derived cells.\n\nConclusion: Juvenile MSCs showed significantly greater migration to SDF-1 and showed greater osteogenic and adipogenic differentiation compared to cells from osteopenic rats, this was true for bone marrow and adipose derived cells. The addition of PTH, increased the osteogenic characteristics and migration of all cells, and further illustrates the possible clinical utility of both PTH and MSCs from various sources in bone regenerative therapies

cell biology↗

bioRxiv2018

Cohesin interacts with a panoply of splicing factors required for cell cycle progression and genomic organization

The cohesin complex regulates sister chromatid cohesion, chromosome organization, gene expression, and DNA repair. Here we report that endogenous human cohesin interacts with a panoply of splicing factors and RNA binding proteins, including diverse components of the U4/U6.U5 tri-snRNP complex and several splicing factors that are commonly mutated in cancer. The interactions are enhanced during mitosis, and the interacting splicing factors and RNA binding proteins follow the cohesin cycle and prophase pathway of regulated interactions with chromatin. Depletion of cohesin-interacting splicing factors results in stereotyped cell cycle arrests and alterations in genomic organization. These data support the hypothesis that splicing factors and RNA binding proteins control cell cycle progression and genomic organization via regulated interactions with cohesin and chromatin.\n\nOne Sentence SummaryEndogenous tagging reveals that cohesin interacts with diverse chromatin-bound splicing factors that regulate cell cycle progression and genomic organization in human cells.

cell biology↗

bioRxiv2018

Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation

Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. Here we report that Usp16, a negative regulator of Bmi1/PRC1 function, modulates the Wnt pathway in mammary epithelia, primary human fibroblasts and MEFs, affecting their expansion and self-renewal potential. In mammary glands, reduced levels of Usp16 increase tissue responsiveness to Wnt, resulting in upregulation of the downstream Wnt target Axin2, expansion of the basal compartment and increased in vitro and in vivo epithelial regeneration. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. In Downs Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. Genetic upregulation of the Wnt pathway in Ts65Dn mice rescues the proliferation defect observed in mammary epithelial cells. All together, these findings link important stem cell regulators like Bmi1/Usp16 and Cdkn2a to Wnt signaling, and have implications for designing therapies for conditions, like DS, aging or degenerative diseases, where the Wnt pathway is hampered.

cell biology↗

bioRxiv2018

Hyperactive Rac1 drives MAPK-independent proliferation in melanoma by assembly of a mechanosensitive dendritic actin network

AbstractCancer cells use a variety of mechanisms to subvert growth regulation and overcome environmental challenges. Often, these same mechanisms enable cancer cells to also develop resistance to targeted therapies. Here, we describe how a hyperactivating mutation of the Rac1 GTPase (Rac1P29S) harnesses Rac1s role as a regulator of actin polymer assembly to sustain cell cycle progression in growth limiting conditions. This proliferative advantage supports metastatic colonization of melanoma cells and confers insensitivity to inhibitors of the mitogen-activated protein kinase (MAPK) pathway, a frequent target for melanoma treatment. Rac1P29S bypasses the MAPK axis through a mechanism that necessitates cell-matrix attachment, however, does not depend on integrin-mediated focal adhesion assembly and focal adhesion kinase signaling. Even without involvement of canonical adhesion signaling, cells carrying the Rac1P29S mutation show elevated traction upon drug treatment and require mechanical resistance from their surrounding matrix to gain a proliferative advantage. We describe an alternative arm for cell mechanosensing, whereby actin polymerization against a matrix of minimal rigidity organizes biochemical cues to drive proliferative signals. Hyperactivation of Rac1 by the P29S mutation channels this pathway in melanoma through Arp 2/3-dependent formation of a constrained actin brush network that results in the inactivation of tumor suppressor NF2/Merlin. These data suggest an alternative mechanism for mechanosensitive growth regulation that can be hijacked by cancer cells to circumvent the adverse conditions of foreign microenvironments or drug treatment.

cell biology↗