Molecular Biology of the Cell (MOL BIOL CELL)

Publisher: American Society for Cell Biology, American Society for Cell Biology

Journal description

Molecular Biology of the Cell, the journal owned and published by The American Society for Cell Biology, publishes papers that describe and interpret results of original research concerning the molecular aspects of cell structure and function. Studies whose scope bridges several areas of biology are particularly encouraged, for example cell biology and genetics. The aim of the Journal is to publish papers describing substantial research progress in full: papers should include all previously unpublished data and methods essential to support the conclusions drawn.

Current impact factor: 4.55

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 4.548
2012 Impact Factor 4.604
2011 Impact Factor 4.942
2010 Impact Factor 5.861
2009 Impact Factor 5.979
2008 Impact Factor 5.558
2006 Impact Factor 6.562
2005 Impact Factor 6.52
2004 Impact Factor 7.517
2003 Impact Factor 7.454
2002 Impact Factor 7.599
2001 Impact Factor 7.7
2000 Impact Factor 8.482
1999 Impact Factor 7.527
1998 Impact Factor 8.256
1997 Impact Factor 8.926
1996 Impact Factor 9.915
1995 Impact Factor 9.376
1994 Impact Factor 10.051
1993 Impact Factor 9.025

Impact factor over time

Impact factor
Year

Additional details

5-year impact 5.35
Cited half-life 7.40
Immediacy index 1.07
Eigenfactor 0.10
Article influence 2.58
Website Molecular Biology of the Cell website
Other titles Molecular biology of the cell, MBC
ISSN 1059-1524
OCLC 24486692
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

American Society for Cell Biology

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Conditions
    • On author's personal website or institutional repository
    • Publisher's version/PDF must be used
    • In Press version must not be used
    • Publisher copyright and source must be acknowledged with citation
    • Must link to publisher version
    • Creative Commons Attribution Non-Commerical Share Alike 3.0 License
    • Articles are placed in PubMed Central after 2 months by publisher
  • Classification
    ​ blue

Publications in this journal

  • Molecular Biology of the Cell 03/2015; 26(6):1007. DOI:10.1091/mbc.E15-01-0011
  • Molecular Biology of the Cell 03/2015; 26(6):1012-1013. DOI:10.1091/mbc.E14-12-1593
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    ABSTRACT: Aquaporin-1 (AQP1) enables greatly enhanced water flux across plasma membranes. The cytosolic carboxy-terminus of AQP1 has two acidic motifs homologous to known carbonic anhydrase II (CAII) binding sequences. CAII colocalizes with AQP1 in the renal proximal tubule. Expression of AQP1 with CAII in Xenopus oocytes or mammalian cells increased water flux relative to AQP1 expression alone. This required the amino terminal sequence of CAII, a region that binds other transport proteins. Expression of catalytically-inactive CAII failed to increase water flux through AQP1. Proximity ligation assays revealed close association of CAII and AQP1, an effect requiring the second acidic cluster of AQP1. This motif was also necessary for CAII to increase AQP1-mediated water flux. Red blood cell ghosts resealed with CAII demonstrated increased osmotic water permeability compared with ghosts resealed with albumin. Water flux across renal cortical membrane vesicles, measured by stopped-flow light scattering, was reduced in CAII-deficient mice compared with wild-type mice. These data are consistent with CAII increasing water conductance through AQP1 by a physical interaction between the two proteins.
    Molecular Biology of the Cell 03/2015; 26(6):1106-1118. DOI:10.1091/mbc.E14-03-0812
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    ABSTRACT: A hallmark of the neuromuscular junction (NMJ) is the high density of acetylcholine receptors (AChRs) in the postsynaptic muscle membrane. The postsynaptic apparatus of the NMJ is organized by agrin secreted from motor neurons. The mechanisms that underlie the focal delivery of AChRs to the adult NMJ are not yet understood in detail. We previously showed that microtubule (MT) capture by the plus end-tracking protein CLASP2 regulates AChR density at agrin-induced AChR clusters in cultured myotubes via PI3 kinase acting through GSK3β. Here we show that knockdown of the CLASP2-interaction partner LL5β by RNAi and forced expression of a CLASP2 fragment blocking the CLASP2/LL5β interaction inhibit microtubule capture. The same treatments impair focal vesicle delivery to the clusters. Consistent with these findings, knockdown of LL5β at the NMJ in vivo reduces the density and insertion of AChRs into the postsynaptic membrane. MT capture and focal vesicle delivery to agrin-induced AChR clusters are also inhibited by microtubule- and actin-depolymerizing drugs, invoking both cytoskeletal systems in MT capture and in the fusion of AChR vesicles with the cluster membrane. Combined our data identify a transport system, organized by agrin through PI3 kinase, GSK3β, CLASP2, and LL5β, for precise delivery of AChR vesicles from the subsynaptic nuclei to the overlying synaptic membrane.
    Molecular Biology of the Cell 03/2015; 26(5):938-951. DOI:10.1091/mbc
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    ABSTRACT: Calponin-related proteins are widely distributed among eukaryotes and involved in signaling and cytoskeletal regulation. Calponin-like (CLIK) repeat is an actin-binding motif found in the C-termini of vertebrate calponins. Although CLIK repeats stabilize actin filaments, other function of these actin-binding motifs is unknown. The Caenorhabditis elegans unc-87 gene encodes actin-binding proteins with seven CLIK repeats. UNC-87 stabilizes actin filaments and is essential for maintenance of sarcomeric actin filaments in striated muscle. Here, we show that two UNC-87 isoforms, UNC-87A and UNC-87B, are expressed in muscle and non-muscle cells in a tissue-specific manner by two independent promoters and exhibit quantitatively different effects on both actin and myosin. Both UNC-87A and UNC-87B have seven CLIK repeats, but UNC-87A has an extra N-terminal extension of ∼190 amino acids. Both UNC-87 isoforms bind to actin filaments and myosin to induce ATP-resistant actomyosin bundles and inhibit actomyosin motility. UNC-87A with an N-terminal extension binds to actin and myosin more strongly than UNC-87B. UNC-87B is associated with actin filaments in non-striated muscle in the somatic gonad, and an unc-87 mutation causes its excessive contraction that is dependent on myosin. These results strongly suggest that proteins with CLIK repeats function as a negative regulator of actomyosin contractility. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-10-1483
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    ABSTRACT: Importin (IMP) superfamily members mediate regulated nucleocytoplasmic transport, which is central to key cellular processes. Although individual IMPα proteins exhibit dynamic synthesis and subcellular localization during cellular differentiation, including during spermatogenesis, little is known of how this affects cell fate. To investigate how IMPαs control cellular development, we conducted a yeast-two-hybrid screen for IMPα2 cargoes in embryonic day 12.5 mouse testis, a site of peak IMPα2 expression coincident with germline masculization. We identified paraspeckle protein 1 (PSPC1), the original defining component of nuclear paraspeckles, as an IMPα2 binding partner. PSPC1-IMPα2 binding in testis was confirmed in immunoprecipitations and pull-downs, and an ELISA-based assay demonstrated direct, high-affinity PSPC1 binding to either IMPα2/IMPβ1 or IMPα6/IMPβ1. Co-expression of full length PSPC1 and IMPα2 in HeLa cells yielded increased PSPC1 localization in nuclear paraspeckles. High throughput image analysis of >3500 cells indicated IMPα2 levels can directly determine PSPC1-positive nuclear speckle numbers and size; a transport-deficient IMPα2 isoform or siRNA knockdown of IMPα2 both reduced endogenous PSPC1 accumulation in speckles. This first validation of an IMPα2 nuclear import cargo in fetal testis provides novel evidence that PSPC1 delivery to paraspeckles, and consequently paraspeckle function, may be controlled by modulated synthesis of specific IMPs. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-01-0678
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    ABSTRACT: Only native polypeptides are released from the endoplasmic reticulum (ER) to be transported at the site of activity. Persistently misfolded proteins are retained and eventually selected for ER-associated degradation (ERAD). The paradox of a structure-based protein quality control is that functional polypeptides may be destroyed if they are architecturally unfit. This has health threatening implications as shown by the numerous "loss-of-function" proteopathies, but also offers chances to intervene pharmacologically to promote bypassing of the quality control inspection and export of the mutant, yet functional protein. Here we challenged the ER of human cells with 4 modular glycopolypeptides designed to alert luminal and membrane protein quality checkpoints. Our analysis reveals the unexpected collaboration of the cytosolic AAA-ATPase p97 and the luminal quality control factor UDP-glucose:glycoprotein glucosyltransferase (UGGT1) in a novel, BiP- and CNX-independent checkpoint. This prevents Golgi transport of a chimera with a native ectodomain that passes the luminal quality control scrutiny, but displays an intramembrane defect. Since human proteopathies may result from impaired transport of functional polypeptides with minor structural defects, identification of quality checkpoints and of treatments to bypass them as shown here upon silencing or pharmacologic inhibition of UGGT1 or p97, may have important clinical implications. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-12-1615
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    ABSTRACT: Chromosome segregation during anaphase depends on chromosome-to-pole motility and pole-to-pole separation. We propose that in Drosophila embryos, the latter process (anaphase B) depends on a persistent kinesin-5-generated interpolar (ip) microtubule (MT) sliding filament mechanism that "engages" to push apart the spindle poles when poleward flux is turned off. Here we investigated the contribution of the midzonal, anti-parallel MT-crosslinking non-motor MAP, Feo, to this "slide-and-flux-or-elongate" mechanism. While Feo homologues in other systems enhance the midzone localization of the MT-MT crosslinking motors, kinesin-4, -5 and -6, the midzone localization of these motors is respectively enhanced, reduced and unaffected by Feo. Strikingly, kinesin-5 localizes all along ipMTs of the anaphase B spindle in the presence of Feo, including at the midzone, but the antibody-induced dissociation of Feo increases kinesin-5 association with the midzone which becomes abnormally narrow, leading to impaired anaphase B and incomplete chromosome segregation. Thus, although Feo and kinesin-5 both preferentially crosslink MTs into anti-parallel polarity patterns, kinesin-5 cannot substitute for loss of Feo function. We propose that Feo controls the organization, stability and motor composition of anti-parallel ipMTs at the midzone, thereby facilitating the kinesin-5-driven sliding filament mechanism underlying proper anaphase B spindle elongation and chromosome segregation. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-12-1631
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    ABSTRACT: Clathrin-mediated endocytosis (CME) is facilitated by a precisely regulated burst of actin assembly. PtdIns(4,5)P2 is an important signaling lipid with conserved roles in CME and actin assembly regulation. Rhomboid family multi-pass, transmembrane proteins regulate diverse cellular processes; however, rhomboid-mediated CME regulation has not been described. We report that yeast lacking the rhomboid protein, Rbd2, exhibit accelerated endocytic site dynamics and premature actin assembly during CME through a PtdIns(4,5)P2-dependent mechanism. Combined genetic and biochemical studies showed that the cytoplasmic tail of Rbd2 binds directly to PtdIns(4,5)P2 and is sufficient for Rbd2's role in actin regulation. Analysis of an Rbd2 mutant with diminished PtdIns(4,5)P2 binding capacity indicates that this interaction is necessary for the temporal regulation of actin assembly during CME. The cytoplasmic tail of Rbd2 appears to modulate PtdIns(4,5)P2 distribution on the cell cortex. The syndapin-like, F-BAR protein Bzz1 functions in a pathway with Rbd2 to precisely control the timing of type-1 myosin recruitment and actin polymerization onset during CME. This work reveals that the previously unstudied rhomboid protein Rbd2 functions in vivo at the nexus of three highly conserved processes: lipid organization, cytoskeletal function and endocytic regulation. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-11-1540
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    ABSTRACT: The aberrant expression of microRNAs (miRNAs) has frequently been reported in cancer studies; miRNAs play roles in development, progression, metastasis and prognosis. Recent studies have indicated that the miRNAs within the Dlk1-Dio3 genomic region are involved in the development of liver cancer, but the role of miR-1188 in hepatocellular carcinoma (HCC) and the pathway by which it exerts its function remain largely unknown. Here, we demonstrate that miR-1188 was significantly down-regulated in mouse hepatoma cells compared with normal liver tissues. Enhanced miR-1188 suppressed cell proliferation, migration and invasion in vitro, and inhibited the tumor growth of HCC cells in vivo. Moreover, overexpressed miR-1188 promoted apoptosis, enhanced caspase-3 activity, and also upregulated the expression of Bax and p53. MiR-1188 directly targeted and negatively regulated Bcl-2 and Sp1. Silencing of Bcl-2 and Sp1 exactly copied the proapoptotic and anti-invasive effect of miR-1188, respectively. Meanwhile, the expression of apoptosis and invasion-related genes such as Vegfa, Fgfr1, and Rprd1b was decreased following enhancement of miR-1188, as determined by gene expression profiling analysis. Taken together, our results highlight an important role for miR-1188 as a tumor suppressor in hepatoma cells, and implicate its potential role in cancer therapy. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-11-1576
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    ABSTRACT: Genetic instability is a hallmark of aneuploidy in budding and fission yeast. All aneuploid yeast strains analyzed to date harbor elevated levels of Rad52-GFP foci, a sign of DNA damage. Here we investigate how continuously elevated levels of DNA damage impact aneuploid cells. We show that Rad52-GFP foci form during S phase, consistent with the observation that DNA replication initiation and elongation are impaired in some aneuploid yeast strains. We furthermore find that although DNA damage is low in aneuploid cells, it nevertheless has dramatic consequences. Many aneuploid yeast strains adapt to DNA damage and undergo mitosis despite the presence of unrepaired DNA leading to cell death. Wild-type cells exposed to low levels of DNA damage exhibit a similar phenotype indicating that adaptation to low levels of unrepaired DNA is a general property of the cell's response to DNA damage. Our results indicate that by causing low levels of DNA damage, whole chromosome aneuploidies lead to DNA breaks that persist into mitosis. Such breaks are the substrate for translocations and deletions that are a hallmark of cancer. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-10-1442
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    ABSTRACT: Axons act like cables, electrically wiring the nervous system. Polar bundles of microtubules (MTs) form their backbones and drive their growth. Plus-end tracking proteins (+TIPs) regulate MT growth dynamics and directionality at their plus ends. However, current knowledge about +TIP functions, mostly derived from work in vitro and in non-neuronal cells, may not necessarily apply to the very different context of axonal MTs. For example, the CLIP family of +TIPs are known MT polymerization promoters in non-neuronal cells. However, we show here that neither Drosophila CLIP-190 nor mammalian CLIP-170 are prominent MT plus end trackers in neurons, which we propose is due to low plus end affinity of the CAP-Gly domain-containing N-terminus and intramolecular inhibition through the C-terminus. Instead, both CLIP-190 and CLIP-170 form F-actin-dependent patches in growth cones, mediated by binding of the coiled-coil domain to Myosin-VI. Since our loss-of-function analyses in vivo and in culture failed to reveal axonal roles for CLIP-190, even in double-mutant combinations with four other +TIPs, we propose that CLIP-190 and -170 are not essential axon extension regulators. Our findings demonstrate that +TIP functions known from non-neuronal cells do not necessarily apply to the regulation of the very distinct MT networks in axons. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-06-1083
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    ABSTRACT: PKCι is essential for the establishment of epithelial polarity and for the normal assembly of tight junctions. We find that PKCι knockdown does not compromise the steady state distribution of most tight junction proteins but results in increased transepithelial resistance (TER) and decreased paracellular permeability. Analysis of the levels of tight junction components demonstrates that claudin-2 protein levels are decreased. However, other tight junction proteins such as claudin-1, ZO-1 and occludin are unchanged. Incubation with an aPKC pseudosubstrate recapitulates the phenotype of PKCι knock down, including increased TER and decreased levels of claudin-2. In addition, overexpression of PKCι results in increased claudin-2 levels. ELISA and coimmunoprecipitation show that the TGN/endosomal small GTPase Rab14 and PKCι interact directly. Immunolabeling shows that PKCι and Rab14 colocalize in both intracellular puncta and at the plasma membrane and that Rab14 expression is required for normal PKCι distribution in cysts in 3D culture. We have shown previously that knockdown of Rab14 results in increased TER and decreased claudin-2. Our results suggest that Rab14 and aPKC interact to regulate trafficking of claudin-2 out of the lysosome directed pathway. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-12-1613
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    ABSTRACT: All known mechanisms of mitotic spindle orientation rely on astral microtubules. We report that even in their absence metaphase spindles in MDCK and HeLa cells are not randomly positioned within their x-z dimension, but preferentially adopt shallow β angles between spindle pole axis and substratum. The non-random spindle positioning was due to constraints imposed by the cell cortex in flat cells that drove spindles that were longer and/or wider than the cell's height into a tilted quasi- diagonal x-z position. In rounder cells, which are taller, fewer cortical constraints made the x-z spindle position more random. Re-establishment of astral microtubule mediated forces aligned the spindle poles with cortical cues parallel to the substratum in all cells. However, in flat cells they frequently caused spindle deformations. Similar deformations were apparent when confined spindles rotated from tilted to parallel positions while MDCK cells progressed from prometaphase to metaphase. The spindle disruptions caused the engagement of the Spindle Assembly Checkpoint. We propose that cell rounding serves to maintain spindle integrity during its positioning. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-08-1330
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    ABSTRACT: Understanding the mechanism underlying axon regeneration is of great practical importance to develop therapeutic treatment for traumatic brain and spinal cord injuries. Dramatic cytoskeleton reorganization occurs at the injury site, and microtubules have been implicated in the regeneration process. Previously we demonstrated that microtubule sliding by conventional kinesin (Kinesin-1) is required for initiation of neurite outgrowth in Drosophila embryonic neurons, and that sliding is developmentally down-regulated when neurite outgrowth is completed. Here we report that mechanical axotomy of Drosophila neurons in culture triggers axonal regeneration and regrowth. Regenerating neurons contain actively sliding microtubules; this sliding, like sliding during initial neurite outgrowth, is driven by Kinesin-1 and is required for axonal regeneration. The injury induces a fast spike of calcium, and depolymerization of microtubules near the injury site, and subsequent formation of local new microtubule arrays with mixed polarity. These events are required for reactivation of microtubule sliding at the initial stages of regeneration. Furthermore, c-Jun N-terminal kinase (JNK) pathway promotes regeneration by enhancing microtubule sliding in injured mature neurons. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-10-1423
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    ABSTRACT: PICK1 is a modular scaffold implicated in synaptic receptor trafficking, containing a PDZ domain, a BAR domain, and an acidic C-terminal tail (ACT). Analysis by small angle x-ray scattering suggests a structural model that places the receptor-binding site of the PDZ domain and membrane-binding surfaces of the BAR and PDZ domains adjacent to each other, on the concave side of the banana-shaped PICK1 dimer. In the model, the ACT of one subunit of the dimer interacts with the PDZ and BAR domains of the other subunit, possibly accounting for autoinhibition. Consistently, full-length PICK1 shows diffuse cytoplasmic localization, but it clusters on vesicle-like structures that colocalize with the trans-Golgi network marker TGN38 upon deletion of either the ACT or PDZ domain. This localization is driven by the BAR domain. Live-cell imaging further reveals that PICK1-associated vesicles undergo fast, non-directional motility, in an F-actin-dependent manner, but deleting the ACT dramatically reduces vesicle speed. Thus, the ACT links PICK1-associated vesicles to a motility factor, likely myosin, but contrary to previous reports PICK1 neither binds nor inhibits Arp2/3 complex. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-10-1448
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    ABSTRACT: Observations in thyroid patients and experimental animals show that the skin is an important target for the thyroid hormones. We have previously shown that deletion in mice of the thyroid hormone nuclear receptors TRα1 and TRβ (the main thyroid hormone binding isoforms), results in impaired epidermal proliferation, hair growth and wound healing. Stem cells located at the bulges of the hair follicles are responsible for hair cycling and contribute to the regeneration of the new epidermis after wounding. Therefore a reduction in the number or function of the bulge stem cells could be responsible for this phenotype. Bulge cells show increased levels of epigenetic repressive marks, can retain bromodeoxyuridine labeling for a long time and have colony formation efficiency (CFE) in vitro. Here, we demonstrate that mice lacking TRs do not have a decrease of the bulge stem cell population. Rather, they show an increase of label-retaining cells (LRCs) in the bulges and enhanced CFE in vitro. A reduced activation of stem cells leading to their accumulation in the bulges is indicated by a strongly reduced response to mobilization by 12-O-tetradecanolyphorbol-13-acetate (TPA). Altered function of the bulge stem cells is associated with aberrant activation of Smad signaling leading to a reduced nuclear accumulation of β-catenin, which is crucial for stem cell proliferation and mobilization. LRCs of TR deficient mice also show increased levels of epigenetic repressive marks. We conclude that thyroid hormone signaling is an important determinant of the mobilization of stem cells out of their niche in the hair bulge. These findings correlate with the skin defects observed in mice and with the alterations found in human thyroid disorders. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-07-1251
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    ABSTRACT: Organelles of the endolysosomal system undergo multiple fission and fusion events to combine sorting of selected proteins to the vacuole with endosomal recycling. This sorting requires a consecutive remodeling of the organelle surface in the course of endosomal maturation. Here, we attempted to dissect the remodeling and fusion machinery on endosomes during the process of endocytosis. We therefore traced selected GFP-tagged endosomal proteins relative to exogenously added fluorescently labeled α-factor on its way from the plasma membrane to the vacuole. Our data reveal that the machinery of endosomal fusion and ESCRT proteins has a similar temporal localization on endosomes, while they precede the retromer cargo recognition complex. Neither deletion of retromer nor the fusion machinery with the vacuole affects this maturation process, though the kinetics seem to be delayed due to ESCRT deletion. Importantly, in strains lacking the active Rab7-like Ypt7 or the vacuolar SNARE fusion machinery, α-factor still proceeds to late endosomes with the same kinetics. This indicates that endosomal maturation is mainly controlled by the early endosomal fusion and remodeling machinery, but not the downstream Rab Ypt7 or the SNARE machinery. Our data thus provide an important further understanding of endosomal biogenesis in the context of cargo sorting. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-08-1318
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    ABSTRACT: Centrosomes nucleate spindle formation, direct spindle pole positioning and are important for proper chromosome segregation during mitosis in most animal cells. We previously reported that centromere protein 32 (CENP-32) is required for centrosome association with spindle poles during metaphase. In this study, we show that CENP-32 depletion seems to release centrosomes from bipolar spindles whose assembly they had previously initiated. Remarkably, the resulting anastral spindles function normally, aligning the chromosomes to a metaphase plate and entering anaphase without detectible interference from the free centrosomes, which appear to behave as free asters in these cells. The free asters, which contain reduced, but significant levels of CDK5RAP2, show weak interactions with spindle microtubules, but do not seem to make productive attachments to kinetochores. Thus, CENP-32 appears to be required for centrosomes to integrate into a fully functional spindle that not only nucleates astral microtubules but is able to nucleate and bind to kinetochore and central spindle microtubules. Additional data suggest that NuMA tethers microtubules at the anastral spindle poles and that Augmin is required for the centrosome detachment following CENP-32-depletion, possibly due to an imbalance of forces within the spindle. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 02/2015; DOI:10.1091/mbc.E14-09-1366
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    ABSTRACT: Disruption of fast axonal transport (FAT) and intracellular Ca(2+) dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by non-excitotoxic activation of calcineurin (CaN). Ca(2+)-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here, we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca(2+) elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca(2+) influx through axonal voltage-gated Ca(2+) channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca(2+) release from the ER. This work establishes a novel role for Ca(2+) dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 01/2015; 26(6). DOI:10.1091/mbc.E14-12-1612