Search

Regulation of SNPH ubiquitination

Pathway analysis of SNPH-associated proteins

Syntaphilin (SNPH) inhibits the movement of mitochondria in tumor cells, preventing their accumulation at the cortical cytoskeleton and limiting the bioenergetics of cell motility and invasion. Although this may suppress metastasis, the regulation of the SNPH pathway is not well understood. Using a global proteomics screen, we show that SNPH associates with multiple regulators of ubiquitin-dependent responses and is ubiquitinated by the E3 ligase CHIP (or STUB1) on Lys111 and Lys153 in the microtubule-binding domain. SNPH ubiquitination did not result in protein degradation, but instead anchored SNPH on tubulin to inhibit mitochondrial motility and cycles of organelle fusion and fission, that is dynamics. Expression of ubiquitination-defective SNPH mutant Lys111→Arg or Lys153→Arg increased the speed and distance traveled by mitochondria, repositioned mitochondria to the cortical cytoskeleton, and supported heightened tumor chemotaxis, invasion, and metastasis in vivo. Interference with SNPH ubiquitination activated mitochondrial dynamics, resulting in increased recruitment of the fission regulator dynamin-related protein-1 (Drp1) to mitochondria and Drp1-dependent tumor cell motility. These data uncover nondegradative ubiquitination of SNPH as a key regulator of mitochondrial trafficking and tumor cell motility and invasion. In this way, SNPH may function as a unique, ubiquitination-regulated suppressor of metastasis.Significance: These findings reveal a new mechanism of metastasis suppression by establishing the role of SNPH ubiquitination in inhibiting mitochondrial dynamics, chemotaxis, and metastasis. Cancer Res; 78(15); 4215–28. ©2018 AACR.

Contents of Supplementary Figures ans Table

Purpose Intraoperative frozen section biopsy is used to reduce the margin positive rate and re-excision rate and has been reported to have high diagnostic accuracy. A majority of breast surgeons in the Republic of Korea routinely perform frozen section biopsy to assess margins intraoperatively, despite its long turnaround time and high resource requirements. This study aims to determine whether omitting frozen section biopsy for intraoperative margin evaluation in selected patients is non-inferior to performing frozen section biopsy in terms of resection margin positivity rate. Methods This study is a phase III, randomized controlled, parallel-group, multicenter non-inferiority clinical trial. Patients meeting the inclusion criteria and providing written informed consent will be randomized to the “frozen section biopsy” or “frozen section biopsy omission” group after lumpectomy. Patients with clinical stage T1–T3 disease who are diagnosed with invasive breast cancer by core-needle biopsy and plan to undergo breast-conserving surgery will be included in this study. If a daughter nodule, non-mass enhancement, or microcalcification is identified on preoperative imaging, these features must be within 1 cm of the main mass for inclusion in the trial. The target sample size is 646 patients per arm. The primary endpoint will be the resection margin positive rate, and the secondary endpoints include the reoperation rate, operating time, residual cancer after reoperation, residual cancer after re-excision according to the frozen section biopsy result, resection volume, patient quality of life, and cost-effectiveness. Discussion This is the first randomized clinical trial utilizing frozen section biopsy for intraoperative margin evaluation and aims to determine the non-inferiority of omitting frozen section biopsy in selected patients compared to performing frozen section biopsy. We expect that this trial will help surgeons perform the procedure more efficiently while ensuring patient safety. Trial Registration ClinicalTrials.gov Identifier: NCT03975179; Clinical Research Information Service Identifier: KCT0004606

A Gram-stain-negative, rod-shaped, and strictly aerobic bacterium designated strain G2-bT was isolated from the marine sediment around Jeju Island, South Korea. Strain G2-bT was found to be catalase- and oxidase-positive, white-pigmented, motile with polar flagellum, and to grow optimally at 25 °C, pH 7.0 in the presence of 4% (w/v) NaCl. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain G2-bT belongs to the genus Salinimonas and was closely related Salinimonas sediminis N102T (96.7% sequence similarity), Salinimonas iocasae KX18D6T (95.4%), Salinimonas lutimaris DPSR-4T (94.7%), and Salinimonas chungwhensis BH030046T (94.6%). Strain G2-bT possessed ubiquinone 8 as the sole respiratory quinone, summed feature 3 and summed feature 8 as the major fatty acids, and phosphatidylethanolamine and phosphatidylglycerol as the major polar lipids. The genome size and G + C content of the strain G2-bT were determined to be 3,765,169 bp, and 49.7%, respectively, as a complete circular genome. Based on the genomic analyses (e.g., average nucleotide identity and digital DNA–DNA hybridization), the strain G2-BT likely represents a new species in the genus Salinimonas, for which we propose to name this novel bacterium Salinimonas marina sp. nov., and the type strain is designated G2-BT (= KCTC 72817T = VTCC 910110T).

The structural and optical properties of InAsxP1-x metamorphic buffers grown by metal–organic chemical vapor deposition on InP (100) substrates have been investigated. High-resolution X-ray reciprocal space mapping around the (115) InP lattice point reveals that the strain relaxations of the InAsxP1-x with x = 0.5, 0.55, and 0.7 are 98%, 92%, and 96%, while the lateral correlation lengths are 17, 62, and 28 nm, respectively. The optical bandgap energy of the InAsP derived from photoreflectance (PR) measurements decreases from 0.819 to 0.621 eV at 300 K when increasing As composition from x = 0.5 to 0.7. The bowing parameter for the optical bandgap of the InAsP is increased with increasing As composition, which is attributable to the increased spontaneous CuPt-type ordering in InAsP. It is found from the excitation power-dependent PR measurement that the InAsxP1-x layers have different degrees of the bandgap redshift due to the reduced thermal conductivity caused by crystal imperfections generated during the strain relaxation process.

Recent research has claimed virulence factors or antimicrobial resistance in commensal or non-pathogenic Neisseria spp. This study aimed to isolate and analyze commensal microorganisms related to the genus Neisseria from the oral cavity of a patient with head and neck cancer. We successfully isolated strain MA1-1 and identified its functional gene contents. Although strain MA1-1 was related to Neisseria flava based on 16S rRNA gene sequence similarity, genomic relatedness analysis revealed that strain MA1-1 was closely related to Neisseria mucosa, reported as a commensal Neisseria species. The strain MA1-1 genome harbored genes for microaerobic respiration and the complete core metabolic pathway with few transporters for nutrients. A number of genes have been associated with virulence factors and resistance to various antibiotics. In addition, the comparative genomic analysis showed that most genes identified in the strain MA1-1 were shared with other Neisseria spp. including two well-known pathogens, Neisseria gonorrhoeae and Neisseria meningitidis. This indicates that the gene content of intra-members of the genus Neisseria has been evolutionarily conserved and is stable, with no gene recombination with other microbes in the host. Finally, this study provides more fundamental interpretations for the complete gene sequence of commensal Neisseria spp. and will contribute to advancing public health knowledge.

Development of efficient surface passivation methods for semiconductor devices is crucial to counter the degradation in their electrical performance owing to scattering or trapping of carriers in the channels induced by molecular adsorption from the ambient environment. However, conventional dielectric deposition involves the formation of additional interfacial defects associated with broken covalent bonds, resulting in accidental electrostatic doping or enhanced hysteretic behavior. In this study, centimeter-scaled van der Waals passivation of transition metal dichalcogenides (TMDCs) is demonstrated by stacking hydrocarbon (HC) dielectrics onto MoSe

We report on the fabrication of wholly polymeric one-dimensional (1-D) photonic crystals (i.e., Bragg reflectors, Bragg mirrors) via solution processing for use in the near (NIR) and the short wave (SWIR) infrared spectrum (1–2 μm) with very high reflectance (R ∼ 90–97%). Facile fabrication of these highly reflective films was enabled by direct access to solution processable, ultrahigh refractive index polymers, termed, Chalcogenide Hybrid Inorganic/Organic Polymers (CHIPs). The high refractive index (n) of CHIPs materials (n = 1.75–2.10) allowed for the production of narrow band IR Bragg reflectors with high refractive index contrast (Δn ∼ 0.5) when fabricated with low n polymers, such as cellulose acetate (n = 1.47). This is the highest refractive index contrast (Δn ∼ 0.5) demonstrated for an all-polymeric Bragg mirror which directly enabled high reflectivity from films with 22 layers or less. Facile access to modular, thin, highly reflective films from inexpensive CHIPs materials offers a new route to ...

We report on the conformal coating of thickness-tunable multilayers directly onto the sulfur (S8) cathodes by the layer-by-layer (LbL) deposition for the significant improvement in the performances of Li–S batteries even without key additives (LiNO3) in the electrolyte. Poly(ethylene oxide) (PEO)/poly(acrylic acid) (PAA) multilayers on a single poly(allylamine hydrochloride) (PAH)/PAA priming bilayer, deposited on the S8 cathodes, effectively protected from the polysulfide leakage, while providing a Li+ ion diffusion channel. As a result, PAH/PAA/(PEO/PAA)3 multilayer-coated cathodes exhibited the highest capacity retention (806 mAh g–1) after 100 cycles at 0.5 C, as well as the high C-rate capability up to 2.0 C. Furthermore, the multilayer coating effectively mitigated the polysulfide shuttle effect in the absent of LiNO3 additives in the electrolyte.

A series of WO3/multiwalled carbon nanotube (MWCNT) nanocomposite sensors was fabricated by bar-coating slurries using different ratios of MWCNTs to WO3 nanoparticles. The morphology, composition, and structure of the fabricated nanocomposites were examined using electron microscopy, X-ray diffraction, ultraviolet and X-ray photoelectron spectroscopy, Raman spectroscopy, and nitrogen adsorption-desorption measurements, with the aim of completely identifying the physical and electronic structures of the nanocomposites. The effects of the different ratios of the nanocomposites on the electrical conductance and NO2 gas sensing properties were examined and compared with the morphological investigation results. The synergetic properties of the nanocomposite sensors were a result of the combined effect of low-doped semiconducting WO3 and metallic MWCNTs. Because nanoscale sensors exhibit a maximal response on the scale of their depletion depth, individual components with conductivities that are either too low or too high cannot meet the condition. Meanwhile, their mixture can establish the required condition for the maximal response which appears as a synergetic effect. Based on this effect, the optimal nanocomposite sensor (0.5 wt% MWCNT) showed a response of ~18 for 5 ppm NO2 at 150 °C with short response/recovery times (~87 s /~300 s). The synergetic effect in nanocomposite sensors cannot be explained by the interfacial Schottky barrier model, which has been used for sensors of agglomerated particles.

We demonstrated the feasibility of using InP (100) substrates, a different indium source, for the synthesis of In2O3 nanowires by the vapor–liquid–solid (VLS) method using a 20-nm-thick Au layer as a catalyst. By varying the thickness of the Au layer and the growth temperature (T), the nanowires showed different morphologies. The nanowires grew along the (100) direction and had perfect crystallinity and lengths up to several hundreds of micrometers. The configured field-effect transistor revealed an n-type behavior with 115 μA of the drain-source current, IDS, under 1.0 V of gate voltage, VDS, at 1.33 × 10−4 kPa of pressure and temperature of 20°C. This result indicates that it is feasible to use different In sources to synthesize In2O3 nanowires by the VLS method for electronic devices.

Ultrathin uracil-complexed CdS nanowires (U-CdS NWs) were synthesized using a facile wet-chemical process and exploited as an effective electron transport layer (ETL) in organic solar cells (OSCs). The U-CdS NW layer acted as a functional interfacial layer between the active organic and inorganic ZnO films; the functional N H and C O groups in uracil passivated the ZnO surface defects and CdS provided a favorable energy band alignment, which facilitated electron transportation. As a result, the power-conversion efficiency (PCE) of the OSC with U-CdS NWs was 3.52% (maximum PCE of 3.7%), which was 22% higher than that of an OSCs with bare ZnO. Moreover, OSCs with U-CdS NWs had two times longer storage lifetimes because of the enhanced interfacial quality and the hydrophobic nature of U-CdS NWs. These results demonstrate the potential of U-CdS NWs for enhancing the efficiency and stability of OSCs and represent an important step toward the commercialization of OSCs.

Viruses promote infection by hijacking the ubiquitin machinery of the host to counteract or redirect cellular processes. Adenovirus encodes two early proteins, E1B55K and E4orf6, that together co-opt a cellular ubiquitin ligase complex to overcome host defences and promote virus production. Adenovirus mutants lacking E1B55K or E4orf6 display defects in viral RNA processing and protein production, but previously identified substrates of the redirected ligase do not explain these phenotypes. Here, we used a quantitative proteomics approach to identify substrates of E1B55K/E4orf6-mediated ubiquitination that facilitate RNA processing. While all currently known cellular substrates of E1B55K and E4orf6 are degraded by the proteasome, we uncovered RNA-binding proteins as high-confidence substrates that are not decreased in overall abundance. We focused on two RNA-binding proteins, RALY and hnRNP-C, which we confirm are ubiquitinated without degradation. Knockdown of RALY and hnRNP-C increased levels of viral RNA splicing, protein abundance and progeny production during infection with E1B55K-deleted virus. Furthermore, infection with E1B55K-deleted virus resulted in an increased interaction of hnRNP-C with viral RNA and attenuation of viral RNA processing. These data suggest that viral-mediated ubiquitination of RALY and hnRNP-C relieves a restriction on viral RNA processing and reveal an unexpected role for non-degradative ubiquitination in the manipulation of cellular processes during virus infection. Adenovirus produces two early proteins, E1B55K and E4orf6, that become components of the host cell ubiquitin ligase complex comprising elongin-B and C, cullin-5 and RBX1. The authors identified new protein substrates that are ubiquitinated by the E1B55K–E4orf6 complex and find that hnRNP-C and RALY play an inhibitory role on late viral RNA transcripts and that this is counteracted by ubiquitination due to a reduction on the capacity of these proteins to interact with viral RNA.

New high-k gate dielectrics are highly necessary in facilitating the continuous down-scaling of metal–oxide–semiconductor devices to the sub-10 nm range. This study presents ultrathin organic hydrocarbon (HC) films as a novel high-k gate insulator for metal–insulator–semiconductor (MIS) devices. During inductively-coupled plasma chemical vapor deposition with CH4 and H2 gases, the growth temperature greatly affects the structure of the carbon layers and consequently their dielectric characteristics. Specifically, sp2-rich dielectric HC layers are formed below 600 °C, whereas highly-ordered sp2-hybridized graphene is formed at 950 °C. The k value of the resulting HC films increases up to a maximum value of 90 at 350 °C. Moreover, the MIS devices exhibit excellent gate-insulating properties, including almost no hysteresis in the capacitance–voltage curve, low leakage current, and high dielectric strength, which surpass those of existing high-k gate oxides. These results reveal that the organic HC films are a promising next-generation high-k gate dielectric material for sub-10 nm node Si and organic semiconductor technologies.

To promote recovery in psychosis, targeting modifiable factors related to recovery is critical. Using more strict definition of full recovery, we examined predictors for recovery in patients with early stage schizophrenia spectrum disorders (SSD) followed up to 6.5 years. The target subjects were 375 patients with early stage SSD who had been over at least 1-year after registration and evaluated. The criteria for full recovery were having the score of the Positive and Negative Syndrome Scale (PANSS) 8-item ≤ 2 and adequate functional recovery for at least 1-year. We performed univariate Cox and stepwise Cox regression in both total and acute patients. In stepwise Cox regression, several independent predictors for recovery, i.e., negative symptoms of the PANSS, duration of untreated psychosis (DUP) and non-professional job were identified in patients with early stage SSD. In acute patients, other factors such as professional job and subjective well-being under neuroleptics were more important. The present study identified independent predictors for recovery modifiable by various psychosocial intervention and early intervention services. Moreover, it highlights the need of providing different treatment strategies depending on clinical status.

The Schlafen gene family encodes for proteins involved in various biological tasks, including cell proliferation, differentiation, and T cell development. Schlafens were initially discovered in mice, and have been studied in the context of cancer biology, as well as their role in protecting cells during viral infection. This protein family provides antiviral barriers via direct and indirect effects on virus infection. Schlafens can inhibit the replication of viruses with both RNA and DNA genomes. In this review, we summarize the cellular functions and the emerging relationship between Schlafens and innate immunity. We also discuss the functions and distinctions of this emerging family of proteins as host restriction factors against viral infection. Further research into Schlafen protein function will provide insight into their mechanisms that contribute to intrinsic and innate host immunity.

Assembly of infectious influenza A viruses (IAV) is a complex process involving transport from the nucleus to the plasma membrane. Rab11A-containing recycling endosomes have been identified as a platform for intracellular transport of viral RNA (vRNA). Here, using high spatiotemporal resolution light-sheet microscopy (~1.4 volumes/second, 330 nm isotropic resolution), we quantify Rab11A and vRNA movement in live cells during IAV infection and report that IAV infection decreases speed and increases arrest of Rab11A. Unexpectedly, infection with respiratory syncytial virus alters Rab11A motion in a manner opposite to IAV, suggesting that Rab11A is a common host component that is differentially manipulated by respiratory RNA viruses. Using two-color imaging we demonstrate co-transport of Rab11A and IAV vRNA in infected cells and provide direct evidence that vRNA-associated Rab11A have altered transport. The mechanism of altered Rab11A movement is likely related to a decrease in dynein motors bound to Rab11A vesicles during IAV infection., Here, using high spatiotemporal resolution light-sheet and fluorescence microscopy, the authors investigate the role of cytoskeletal components on the intracellular transport of Rab11A and influenza virus (IAV) vRNP), and show a preference for Rab11A movement along microtubules that is not essential for IAV vRNP transport.

Solar absorber Cu2ZnSnS4 (CZTS) films were uniformly deposited on Si/Mo substrates via a facile, cost-effective chemical bath deposition (CBD) by using ribonucleic acid (RNA) nucleobase uracil as the functional building block. The functional sites of uracil, i.e., C O and N H, played a critical role in the complexation of metals via uracil-quartet functional architectures. Stable metal–uracil complexes significantly affected the growth kinetics, enhancing the uniform delivery of multimetal components into films and suppressing the undesirable formation of CuS particles. CZTS films obtained with the addition of 0.05 and 0.5 M uracil exhibited a smooth surface morphology and significantly improved photoconductive performance. The developed RNA-nucleobase-mediated CBD method demonstrates promise as multicomponent compound absorber films, including CZTS and CuInGaSe2, in cost-effective solar cells.

The NFAT family of transcription factors plays an important role in immune system development and function. NFATc1 and NFATc2 are highly expressed in peripheral T cells, and several isoforms are produced via the use of different promoters and polyadenylation sites. The specific isoforms with relatively long C-termini, NFATc1/C and NFATc2/A, have been shown to be modified by SUMO within their specific C-terminal regions, which regulates NFAT protein localization and transactivation activity. Here, we demonstrate that an isoform NFATc1/A, which has a short C-terminus and does not contain the sumoylation sites found in the long isoforms, is also modified by SUMO. NFATc1/A sumoylation increased with low level expression of SUMO E3 ligases, specifically PIAS1, PIAS3, and PIASy, in co-transfected cells. PIAS3 interacted with NFATc1/A and an active site mutant failed to promote NFATc1/A sumoylation, indicating a role for PIAS3 as a SUMO E3 ligase. A lysine residue at 351 within the central regulatory domain was identified as the major SUMO attachment site in both co-transfection and in vitro assays. Sumoylation of NFATc1/A did not affect nuclear translocation upon ionomycin and phorbol 12-myristate 13-acetate treatment. However, although sumoylation of NFATc1/A slightly increased protein stability, it inhibited transactivation activity for reporter genes driven by promoters containing NFAT sites. Our results indicate that the transactivation activity of NFATc1/A is negatively regulated by PIAS protein-mediated sumoylation, and that SUMO is a general regulator of NFAT family members with either long or short C-termini.