Publications
222 results found
Way M, 2017, Chromosomal breaks during mitotic catastrophe trigger gamma H2AX-ATM-p53-mediated apoptosis (vol 124, pg 2951, 2011), JOURNAL OF CELL SCIENCE, Vol: 130, Pages: 1979-1979, ISSN: 0021-9533
Way M, 2017, Relating to the retraction of: Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration (vol 129, pg 3203, 2016), JOURNAL OF CELL SCIENCE, Vol: 130, Pages: 1856-1856, ISSN: 0021-9533
Durkin CH, Leite F, Cordeiro JV, et al., 2017, RhoD inhibits RhoC-ROCK-dependent cell contraction via PAK6, Developmental Cell, Vol: 41, Pages: 315-329.e7, ISSN: 1534-5807
RhoA-mediated regulation of myosin-II activity in the actin cortex controls the ability of cells to contract and bleb during a variety of cellular processes, including cell migration and division. Cell contraction and blebbing also frequently occur as part of the cytopathic effect seen during many different viral infections. We now demonstrate that the vaccinia virus protein F11, which localizes to the plasma membrane, is required for ROCK-mediated cell contraction from 2 hr post infection. Curiously, F11-induced cell contraction is dependent on RhoC and not RhoA signaling to ROCK. Moreover, RhoC-driven cell contraction depends on the upstream inhibition of RhoD signaling by F11. This inhibition prevents RhoD from regulating its downstream effector Pak6, alleviating the suppression of RhoC by the kinase. Our observations with vaccinia have now demonstrated that RhoD recruits Pak6 to the plasma membrane to antagonize RhoC signaling during cell contraction and blebbing.
Postigo A, Ramsden AE, Howell M, et al., 2017, Cytoplasmic ATR activation promotes vaccinia virus genome replication, Cell Reports, Vol: 19, Pages: 1022-1032, ISSN: 2211-1247
In contrast to most DNA viruses, poxviruses replicate their genomes in the cytoplasm without host involvement. We find that vaccinia virus induces cytoplasmic activation of ATR early during infection, before genome uncoating, which is unexpected because ATR plays a fundamental nuclear role in maintaining host genome integrity. ATR, RPA, INTS7, and Chk1 are recruited to cytoplasmic DNA viral factories, suggesting canonical ATR pathway activation. Consistent with this, pharmacological and RNAi-mediated inhibition of canonical ATR signaling suppresses genome replication. RPA and the sliding clamp PCNA interact with the viral polymerase E9 and are required for DNA replication. Moreover, the ATR activator TOPBP1 promotes genome replication and associates with the viral replisome component H5. Our study suggests that, in contrast to long-held beliefs, vaccinia recruits conserved components of the eukaryote DNA replication and repair machinery to amplify its genome in the host cytoplasm.
Way M, 2017, 2016 Winner: Viswanadh Madugula., J Cell Sci, Vol: 130
Sansregret L, Patterson JO, Dewhurst S, et al., 2017, APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability, CANCER DISCOVERY, Vol: 7, Pages: 218-233, ISSN: 2159-8274
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- Citations: 73
Ahmad SA, Way M, 2017, New Editor on Journal of Cell Science, JOURNAL OF CELL SCIENCE, Vol: 130, Pages: 303-303, ISSN: 0021-9533
Balasus D, Way M, Fusilli C, et al., 2016, The association of variants in PNPLA3 and GRP78 and the risk of developing hepatocellular carcinoma in an Italian population., Oncotarget, Vol: 7, Pages: 86791-86802
Hepatocellular carcinoma (HCC) has one of the worst prognoses amongst all malignancies. It commonly arises in patients with established liver disease and the diagnosis often occurs at an advanced stage. Genetic variations, such as single nucleotide polymorphisms (SNPs), may alter disease risk and thus may have use as predictive markers of disease outcome. The aims of this study were (i) to assess the association of two SNPs, rs430397 in GRP78 and rs738409 in PNPLA3 with the risk of developing HCC in a Sicilian association cohort and, (ii) to use a machine learning technique to establish a predictive combinatorial phenotypic model for HCC including rs430397 and rs738409 genotypes and clinical and laboratory attributes. The controls comprised of 304 healthy subjects while the cases comprised of 170 HCC patients the majority of whom had hepatitis C (HCV)-related cirrhosis. Significant associations were identified between the risk of developing HCC and both rs430397 (p=0.0095) and rs738409 (p=0.0063). The association between rs738409 and HCC was significantly stronger in the HCV positive cases. In the best prediction model, represented graphically by a decision tree with an acceptable misclassification rate of 17.0%, the A/A and G/A genotypes of the rs430397 variant were fixed and combined with the three rs738409 genotypes; the attributes were age, sex and alcohol. These results demonstrate significant associations between both rs430397 and rs738409 and HCC development in a Sicilian cohort. The combinatorial predictive model developed to include these genetic variants may, if validated in independent cohorts, allow for earlier diagnosis of HCC.
Way M, 2016, Journal of Cell Science is going green, JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 3519-3519, ISSN: 0021-9533
Snetkov X, Weisswange I, Pfanzelter J, et al., 2016, NPF motifs in the vaccinia virus protein A36 recruit intersectin-1 to promote Cdc42:N-WASP-mediated viral release from infected cells, Nature Microbiology, Vol: 1, Pages: 1-11, ISSN: 2058-5276
During its egress, vaccinia virus transiently recruits AP-2 and clathrin after fusion with the plasma membrane. This recruitment polarizes the viral protein A36 beneath the virus, enhancing actin polymerization and the spread of infection. We now demonstrate that three NPF motifs in the C-terminus of A36 recruit AP-2 and clathrin by interacting directly with the Epsin15 homology domains of Eps15 and intersectin-1. A36 is the first identified viral NPF motif containing protein shown to interact with endocytic machinery. Vaccinia still induces actin tails in the absence of the A36 NPF motifs. Their loss, however, reduces the cell-to-cell spread of vaccinia. This is due to a significant reduction in virus release from infected cells, as the lack of intersectin-1 recruitment leads to a loss of Cdc42 activation, impairing N-WASP-driven Arp2/3-mediated actin polymerization. Our results suggest that initial A36-mediated virus release plays a more important role than A36-driven super-repulsion in promoting the cell-to-cell spread of vaccinia.During vaccinia virus egress, intracellular enveloped virus (IEV) fuses with the plasma membrane to liberate infectious virions into the surrounding environment1. Cell-associated enveloped virions (CEVs) that remain attached to the outside of the cell, however, stimulate Arp2/3 complex-dependent actin polymerization to enhance their spread into neighbouring cells2–5. CEVs stimulate actin polymerization by inducing Src and Abl family kinase-mediated phosphorylation of tyrosine 112 and 132 of the integral viral membrane protein A36 (refs 3,6–9). When phosphorylated, tyrosine 112 recruits Nck, which interacts with a complex of WIP and N-WASP, the latter of which stimulates Arp2/3 complex-mediated actin polymerization3,10–13. Phosphorylation of tyrosine 132 of A36 leads to the recruitment of Grb2, which helps stabilize Nck, WIP and N-WASP to enhance actin polymerization6,12,13. In addition, Cdc42, an activator of N-WASP, a
Way M, 2016, The good, the bad and the median, JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 3205-3205, ISSN: 0021-9533
Sirianni A, Krokowski S, Lobato-Márquez D, et al., 2016, Mitochondria mediate septin cage assembly to promote autophagy of Shigella, EMBO Reports, Vol: 17, Pages: 1-15, ISSN: 1469-221X
Septins, cytoskeletal proteins with well-characterised roles in cytokinesis, form cage-like structures around cytosolic Shigella flexneri and promote their targeting to autophagosomes. However, the processes underlying septin cage assembly, and whether they influence S. flexneri proliferation, remain to be established. Using single cell analysis, we show that septin cages inhibit S. flexneri proliferation. To study mechanisms of septin cage assembly, we used proteomics and found mitochondrial proteins associate with septins in S. flexneriinfected cells. Strikingly, mitochondria associated with S. flexneri promote septin assembly into the cages that entrap bacteria for autophagy. We demonstrate that the cytosolic GTPase dynamin-related protein 1 (Drp1) interacts with septins to enhance mitochondrial fission. To avoid autophagy, actin-polymerising Shigella fragment mitochondria to escape from septin caging. Our results have demonstrated a role for mitochondria in anti-Shigella autophagy, and uncovered a fundamental link between septin assembly and mitochondria.
Ahmad SA, Way M, 2016, New Editor on Journal of Cell Science, JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 2287-2287, ISSN: 0021-9533
Abella JVG, Way M, 2016, Actin'g against the Ball and Chain, DEVELOPMENTAL CELL, Vol: 37, Pages: 11-12, ISSN: 1534-5807
Way M, 2016, 2015 Winner: Monika Zwerger., J Cell Sci, Vol: 129, Pages: 1083-1084
Way M, 2016, Sirtuin-3 modulates Bak- and Bax-dependent apoptosis (Expression of Concern of Vol 126, Pg 274, 2013), JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 871-871, ISSN: 0021-9533
Way M, 2016, Mitoneet mediates TNFα-induced necroptosis promoted by exposure to fructose and ethanol (Expression of Concern of Vol 127, Pg 896, 2014), JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 872-872, ISSN: 0021-9533
Way M, 2016, Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by sirtuin-3 (Expression of Concern of Vol 123, Pg 4117, 2010), JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 869-869, ISSN: 0021-9533
Way M, 2016, Sirtuin-3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria (Expression of Concern of Vol 123, Pg 894, 2010), JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 868-868, ISSN: 0021-9533
Way M, 2016, GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis (Expression of Concern of Vol 125, Pg 2995, 2012), JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 870-870, ISSN: 0021-9533
Fernandez-Escobar M, Luis Najera J, Baldanta S, et al., 2016, Suppression of NYVAC Infection in HeLa Cells Requires RNase L but Is Independent of Protein Kinase R Activity, JOURNAL OF VIROLOGY, Vol: 90, Pages: 2135-2141, ISSN: 0022-538X
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- Citations: 1
Abella JVG, Galloni C, Pernier J, et al., 2016, Isoform diversity in the Arp2/3 complex determines actin filament dynamics, Nature Cell Biology, Vol: 18, Pages: 76-86, ISSN: 1465-7392
The Arp2/3 complex consists of seven evolutionarily conserved subunits (Arp2, Arp3 and ARPC1–5) and plays an essential role in generating branched actin filament networks during many different cellular processes. In mammals, however, the ARPC1 and ARPC5 subunits are each encoded by two isoforms that are 67% identical. This raises the possibility that Arp2/3 complexes with different properties may exist. We found that Arp2/3 complexes containing ARPC1B and ARPC5L are significantly better at promoting actin assembly than those with ARPC1A and ARPC5, both in cells and in vitro. Branched actin networks induced by complexes containing ARPC1B or ARPC5L are also disassembled ∼2-fold slower than those formed by their counterparts. This difference reflects the ability of cortactin to stabilize ARPC1B- and ARPC5L- but not ARPC1A- and ARPC5-containing complexes against coronin-mediated disassembly. Our observations demonstrate that the Arp2/3 complex in higher eukaryotes is actually a family of complexes with different properties.
Ahmad SA, Way M, 2015, Plus ca change..., JOURNAL OF CELL SCIENCE, Vol: 128, Pages: 4247-4248, ISSN: 0021-9533
Buch S, Stickel F, Trépo E, et al., 2015, A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis., Nat Genet, Vol: 47, Pages: 1443-1448
Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
Leite F, Way M, 2015, The role of signalling and the cytoskeleton during Vaccinia Virus egress, VIRUS RESEARCH, Vol: 209, Pages: 87-99, ISSN: 0168-1702
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- Citations: 32
Keppler SJ, Gasparrini F, Burbage M, et al., 2015, Wiskott-Aldrich syndrome interacting protein deficiency uncovers the role of the co-receptor CD19 as a generic hub for PI3 kinase signaling in B cells, Immunity, Vol: 43, Pages: 660-673, ISSN: 1074-7613
Humans with Wiskott-Aldrich syndrome display a progressive immunological disorder associated with compromised Wiskott-Aldrich Syndrome Interacting Protein (WIP) function. Mice deficient in WIP recapitulate such an immunodeficiency that has been attributed to T cell dysfunction; however, any contribution of B cells is as yet undefined. Here we have shown that WIP deficiency resulted in defects in B cell homing, chemotaxis, survival, and differentiation, ultimately leading to diminished germinal center formation and antibody production. Furthermore, in the absence of WIP, several receptors, namely the BCR, BAFFR, CXCR4, CXCR5, CD40, and TLR4, were impaired in promoting CD19 co-receptor activation and subsequent PI3 kinase (PI3K) signaling. The underlying mechanism was due to a distortion in the actin and tetraspanin networks that lead to altered CD19 cell surface dynamics. In conclusion, our findings suggest that, by regulating the cortical actin cytoskeleton, WIP influences the function of CD19 as a general hub for PI3K signaling.
Brama E, Peddie CJ, Jones ML, et al., 2015, Standard fluorescent proteins as dual-modality probes for correlative experiments in an integrated light and electron microscope, Journal of Chemical Biology, Vol: 8, Pages: 179-188, ISSN: 1864-6158
Integrated light and electron microscopes (ILEMs) will enable a new generation of high-precision correlative imaging experiments. To fully exploit these systems, samples must contain dual-modality probes that highlight the position of macromolecules in the context of cell ultrastructure. We demonstrate that the fluorescent proteins (FPs) GFP (green), YFP (yellow) and mCherry can be used as dual-modality probes for ILEM when preserved using the in-resin fluorescence (IRF) technique, which delivers stable active fluorophores in lightly stained, resin-embedded cells and tissues. However, we found that vacuum pressure in the ILEM affects the photophysics of FPs in IRF sections. Here, we show that reducing the vacuum pressure reduces fluorescence intensity of GFP and YFP, which is a consequence of water extraction from the sample and is reversible on re-creation of partial pressure with water vapour (but not oxygen or nitrogen gas). We also find that, although fluorescence intensity is reduced at a partial pressure of 200 Pa (created using water vapour), the FP intensity is remarkably stable over time in vacuum and resistant to photobleaching during imaging. We are thus able to define imaging strategies for standard FPs acting as dual-modality probes in a single ‘multi-colour’ integrated microscope system.
Way M, 2015, Andrew Ewald takes the helm of first JCS Guest Editorship, JOURNAL OF CELL SCIENCE, Vol: 128, Pages: 2743-2743, ISSN: 0021-9533
Hanc P, Fujii T, Iborra S, et al., 2015, Structure of the Complex of F-Actin and DNGR-1, a C-Type Lectin Receptor Involved in Dendritic Cell Cross-Presentation of Dead Cell-Associated Antigens, IMMUNITY, Vol: 42, Pages: 839-849, ISSN: 1074-7613
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- Citations: 51
Way M, McQuillin A, Saini J, et al., 2015, Genetic variants in or near ADH1B and ADH1C affect susceptibility to alcohol dependence in a British and Irish population., Addict Biol, Vol: 20, Pages: 594-604
Certain single nucleotide polymorphisms (SNPs) in genes encoding alcohol dehydrogenase (ADH) enzymes confer a significant protective effect against alcohol dependence syndrome (ADS) in East Asian populations. Recently, attention has focused on the role of these SNPs in determining ADS risk in European populations. To further elucidate these associations, SNPs of interest in ADH1B, ADH1C and the ADH1B/1C intergenic region were genotyped in a British and Irish population (ADS cases n = 1076: controls n = 1027) to assess their relative contribution to ADS risk. A highly significant, protective association was observed between the minor allele of rs1229984 in ADH1B and ADS risk [allelic P = 8.4 × 10(-6) , odds ratio (OR) = 0.26, 95 percent confidence interval, 0.14, 0.49]. Significant associations were also observed between ADS risk and the ADH1B/1C intergenic variant, rs1789891 [allelic P = 7.2 × 10(-5) , OR = 1.4 (1.2, 1.6)] and three non-synonymous SNPs rs698, rs1693482 and rs283413 in ADH1C. However, these associations were not completely independent; thus, while the ADH1B rs1229984 minor allele association was independent of those of the intergenic variant rs1789891 and the three ADH1C variants, the three ADH1C variants were not individually independent. In conclusion, the rare ADH1B rs1229984 mutation provides significant protection against ADS in this British and Irish population; other variants in the ADH gene cluster also alter ADS risk, although the strong linkage disequilibrium between SNPs at this location precluded clear identification of the variant(s) driving the associations.
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