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Journal of Biological Chemistry

Dan Wu, Veerle De Wever, Rita Derua, Claudia Winkler, Monique Beullens, Aleyde van Eynde, Mathieu Bollen
The protein Ser/Thr phosphatase PP1 catalyzes an important fraction of protein dephosphorylation events and forms highly specific holoenzymes through an association with 'regulatory interactors of protein phosphatase one' (RIPPOs). The functional characterization of individual PP1 holoenzymes is hampered by the lack of straightforward strategies for substrate mapping. Since efficient substrate recruitment often involves binding to both PP1 and its associated RIPPO, here we examined whether PP1-RIPPO fusions can be used to trap substrates for further analysis...
August 16, 2018: Journal of Biological Chemistry
Lina Sun, Mayumi Ishihara, Dustin R Middleton, Michael Tiemeyer, Fikri Y Avci
The glycan shield on the envelope glycoprotein gp120 of human immunodeficiency virus 1 (HIV-1) has drawn immense attention as a vulnerable site for broadly neutralizing antibodies (bNAbs) and for its significant impact on host adaptive immune response to HIV-1. Glycosylation sites and glycan composition/structure at each site on gp120 along with the interactions of gp120 glycan-shield with bNAbs have been extensively studied. However, a method for directly and selectively tracking gp120 glycans has been lacking...
August 16, 2018: Journal of Biological Chemistry
Songhua Li, Kota Sato, William C Gordon, Michael Sendtner, Nicolas G Bazan, Minghao Jin
The retinal pigment epithelium (RPE)-dependent visual cycle provides 11-cis-retinal to opsins in the photoreceptor outer segments to generate functional visual pigments that initiate phototransduction in response to light stimuli. Both RPE65 isomerase of the visual cycle and the rhodopsin visual pigment have recently been identified as critical players in mediating light-induced retinal degeneration. These findings suggest that the expression and function of RPE65 and rhodopsin need to be coordinately controlled to sustain normal vision and to protect the retina from photodamage...
August 16, 2018: Journal of Biological Chemistry
Jiji T Kurup, Benjamin L Kidder
RNA has been shown to interact with various proteins to regulate chromatin dynamics and gene expression. However, it is unknown whether RNAs associate with epigenetic marks such as post-translational modifications of histones, including histone 4 lysine 20 trimethylation (H4K20me3) or trimethylated histone 3 lysine 4 (H3K4me3), to regulate chromatin and gene expression. Here, we used chromatin-associated RNA immunoprecipitation (CARIP) followed by next-generation sequencing (CARIP-Seq) to survey RNAs associated with H4K20me3 and H3K4me3-marked chromatin on a global-scale in embryonic stem (ES) cells...
August 16, 2018: Journal of Biological Chemistry
Saurav De, Fawziya Karim, Ezechielle Kiessu, Leah Cushing, Lih-Ling Lin, Jean-Laurent Casanova, Anne Puel, Cyrille Hoarau, Pegah Ghandil, Vikram R Rao
Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a central regulator of innate immune signaling, controlling IL-1R and Toll-like receptor (TLR)-mediated responses and containing both scaffolding and kinase activities. Humans deficient in IRAK4 activity have autosomal recessive primary immune deficiency (PID). Here, we characterized the molecular mechanism of dysfunction of two IRAK4 PID variants, G298D and the compound variant R12C (R12C/R391H/T458I). Using these variants and the kinase-inactive D329A variant to delineate the contributions of IRAK4's scaffolding and kinase activities to IL1R signaling, we found that the G298D variant is kinase-inactive and expressed at extremely low levels, acting functionally as a null mutation...
August 16, 2018: Journal of Biological Chemistry
Alan Dempsey, Sinead E Keating, Michael Carty, Andrew G Bowie
Host pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) detect viruses and other pathogens, inducing production of cytokines that cause inflammation and mobilize cells to control infection. Vaccinia virus (VACV) encodes proteins that antagonize these host innate immune responses, and elucidating the mechanisms of action of these viral proteins helped shed light on PRR signalling mechanisms. The VACV virulence factor E3 is one of the most intensely studied VACV proteins and has multiple effects on host cells, many of which cannot be explained by the currently known cellular targets of E3...
August 15, 2018: Journal of Biological Chemistry
Sylvia Hoff, Daniel Epting, Nathalie Falk, Sophie Schroda, Daniela A Braun, Jan Halbritter, Friedhelm Hildebrandt, Albrecht Kramer-Zucker, Carsten Bergmann, Gerd Walz, Soeren S Lienkamp
Nephronophthisis (NPH) is an autosomal recessive renal disease leading to kidney failure in children and young adults. The protein products of the corresponding genes (NPHPs) are localized in primary cilia or their appendages. Only about 70% of affected individuals have a mutation in one of 100 renal ciliopathy genes, and no unifying pathogenic mechanism has been identified. Recently, some NPHPs, NIMA-related kinase 8 (NEK8), and centrosomal protein 164 (CEP164) have been found to act in the DNA damage response pathway and to contribute to genome stability...
August 15, 2018: Journal of Biological Chemistry
Duco Koenis, Lejla Medzikovic, Mariska Vos, Thijs J Beldman, Pieter B van Loenen, Claudia M van Tiel, Anouk Aj Hamers, Iker Otermin Rubio, Vivian de Waard, Carlie de Vries
Gene targeting via homologous recombination can occasionally result in incomplete disruption of the targeted gene. Here, we show that a widely-used Nur77-deficient transgenic mouse model expresses a truncated protein encoding for part of the amino-terminal domain of nuclear receptor Nur77. This truncated Nur77 protein is absent in a newly developed Nur77-deficient mouse strain generated using Cre-Lox recombination. Comparison of these two mouse strains using immunohistochemistry, flow cytometry and colony-forming assays shows that homologous recombination-derived Nur77-deficient mice - but not wild-type or Cre-Lox-derived Nur77-deficient mice - suffer from liver immune cell infiltrates, loss of splenic architecture, and increased numbers of bone marrow hematopoietic stem cells and splenic colony-forming cells with age...
August 15, 2018: Journal of Biological Chemistry
Wanting Yu, Yang Zhan, Boxin Xue, Yanpeng Dong, Yanfeng Wang, Ping Jiang, Aibing Wang, Yujie Sun, Yi Yang
Porcine circovirus type 2 (PCV2) is one of the smallest, non-enveloped, single-stranded DNA viruses. The PCV2 capsid protein (Cap) is the sole viral structural protein and main antigenic determinant. Previous sequence analysis has revealed that the N-terminus of the PCV2 Cap contains a nuclear localization signal (NLS) enriched in positively charged residues. Here, we report that PCV2's NLS can function as a cell-penetrating peptide (CPP). We observed that this NLS can carry macromolecules, e.g. enhanced GFP (EGFP), into cells when they are fused to the NLS, indicating that it can function as a CPP, similar to the classical CPP derived from HIV type 1 trans-activator of transcription protein (HIV TAT)...
August 14, 2018: Journal of Biological Chemistry
Kazuei Igarashi, Keiko Kashiwagi
Polyamines putrescine, spermidine, and spermine have numerous roles in the growth of both prokaryotic and eukaryotic cells.  For example, it is well known that putrescine and spermidine are strongly involved in proliferation and viability of Escherichia coli cells.  Studies of polyamine functions and distributions in E. coli cells have revealed that polyamines mainly exist as an RNA-polyamine complex.  Polyamines stimulate the assembly of 30S ribosomal subunits and thereby increase general protein synthesis 1...
August 14, 2018: Journal of Biological Chemistry
Anne E Robinson, Jessica E Lowe, Eun-Ik Koh, Jeffrey P Henderson
Invasive gram-negative bacteria often express multiple virulence-associated metal ion chelators to combat host-mediated metal deficiencies. Escherichia coli , Klebsiella , and Yersinia pestis isolates encoding the Yersinia High Pathogenicity Island (HPI) secrete yersiniabactin (Ybt), a metallophore originally shown to chelate iron ions during infection. However, our recent demonstration that Ybt also scavenges copper ions during infection led us to question whether it might be capable of retrieving other metals as well...
August 14, 2018: Journal of Biological Chemistry
Wenjing Li, Xiahui Xiong, Amro Abdalla, Salvador Alejo, Linyu Zhu, Fei Lu, Hong Sun
The MET proto-oncogene encoded receptor tyrosine kinase MET and AXL receptor tyrosine kinase (AXL) are independently operating receptor tyrosine kinases (RTKs) that are functionally associated with aggressive and invasive cancer cell growth. However, how MET and AXL regulate the migratory properties of cancer cells remains largely unclear. We report here that addition of hepatocyte growth factor (HGF), the natural ligand of MET, to serum-starved human glioblastoma cells induces the rapid activation of both MET and AXL and formation of highly polarized MET-AXL clusters on the plasma membrane...
August 14, 2018: Journal of Biological Chemistry
Dwight M Chambers, Leandro Moretti, Jennifer J Zhang, Spencer W Cooper, Davis M Chambers, Philip J Santangelo, Thomas H Barker
Transforming growth factor-beta (TGFβ) signaling through SMAD2/3 is an important driver of pathological fibrosis in multiple organ systems. TGFβ signaling and extracellular matrix (ECM) stiffness form an unvirtuous pathological circuit in which matrix stiffness drives activation of latent TGFβ, and TGFβ signaling then drives cellular stress and ECM synthesis. Moreover, ECM stiffness also appears to sensitize cells to exogenously activated TGFβ through unknown mechanisms. Here, using human fibroblasts, we explored the effect of ECM stiffness on a putative inner nuclear membrane protein, LEM domain-containing protein 3 (LEMD3), which is physically connected to the cell's actin cytoskeleton and inhibits TGFβ signaling...
August 14, 2018: Journal of Biological Chemistry
Christoph U Schräder, Andrea Heinz, Petra Majovsky, Berin Karaman, Jürgen Brinckmann, Wolfgang Sippl, Christian E H Schmelzer
Elastin is an essential vertebrate protein responsible for the elasticity of force-bearing tissues such as those of the lungs, blood vessels, and skin. One of the key features required for the exceptional properties of this durable biopolymer is the extensive covalent cross-linking between domains of its monomer molecule tropoelastin. To date, elastin's exact molecular assembly and mechanical properties are poorly understood. Here, using bovine elastin, we investigated the different types of cross-links in mature elastin to gain insight into its structure...
August 14, 2018: Journal of Biological Chemistry
Seunghwan Choi, Minsik Park, Joohwan Kim, Wonjin Park, Suji Kim, Dong-Keon Lee, Jong Yun Hwang, Jongseon Choe, Moo-Ho Won, Sungwoo Ryoo, Kwon-Soo Ha, Young-Guen Kwon, Young-Myeong Kim
cGMP-dependent protein kinase 1 (PKG1) plays an important role in nitric oxide (NO)/cGMP-mediated maintenance of vascular smooth muscle cell (VSMC) phenotype and vasorelaxation. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), have long been understood to mediate several inflammatory vascular diseases. However, the underlying mechanism of TNF-α-dependent inflammatory vascular disease is unclear. Here, we found that TNF-α treatment decreased PKG1 expression in cultured VSMCs, which correlated with NF-κB-dependent biogenesis of miR-155-5p that targeted the 3'-untranslated region of PKG1 mRNA...
August 13, 2018: Journal of Biological Chemistry
Manickam Yogavel, Joanne E Nettleship, Akansha Sharma, Karl Harlos, Abhishek Jamwal, Rini Chaturvedi, Manmohan Sharma, Vitul Jain, Jyoti Chhibber-Goel, Amit Sharma
The genomes of the malaria-causing Plasmodium parasites encode a protein fused of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) domains that catalyze sequential reactions in the folate biosynthetic pathway. Whereas higher organisms derive folate from their diet and lack the enzymes for its synthesis, most eubacteria and a number of lower eukaryotes including malaria parasites synthesize tetrahydrofolate via DHPS. Plasmodium falciparum ( Pf ) and Plasmodium vivax ( Pv ) HPPK-DHPSs are currently targets of drugs like sulfadoxine (SDX)...
August 13, 2018: Journal of Biological Chemistry
George J N Tetley, Aydan Szeto, Adam J Fountain, Helen R Mott, Darerca Owen
Wiskott-Aldrich syndrome protein (WASP) activates the actin-related protein 2/3 homolog (Arp2/3) complex and regulates actin polymerization in a physiological setting. Cell division cycle 42 (Cdc42) is a key activator of WASP, which binds Cdc42 through a Cdc42/Rac-interactive binding (CRIB)-containing region that defines a subset of Cdc42 effectors. Here, using site-directed mutagenesis, binding affinity determination and kinetic assays, we report the results of an investigation into the energetic contributions of individual WASP residues to both the Cdc42-WASP binding interface and the kinetics of complex formation...
August 13, 2018: Journal of Biological Chemistry
Elizabeth J White, Gabriel Gyulay, Šárka Lhoták, Magdalena M Szewczyk, Taryne Chong, Mark T Fuller, Omid Dadoo, Alison E Fox-Robichaud, Richard C Austin, Bernardo Trigatti, Suleiman A Igdoura
Atherosclerosis is a complex disease that involves alterations in lipoprotein metabolism and inflammation. Protein and lipid glycosylation events, such as sialylation, contribute to the development of atherosclerosis and are regulated by specific glycosidases, including sialidases. To evaluate the effect of the sialidase neuraminidase 1 (NEU1) on atherogenesis, here we generated apolipoprotein E (ApoE)-deficient mice that express hypomorphic levels of NEU1 ( Neu1hypo Apoe-/- ). We found that the hypomorphic NEU1 expression in male Apoe-/- mice reduces serum levels of very-low-density lipoprotein (VLDL) and LDL cholesterol, diminishes infiltration of inflammatory cells into lesions, and decreases aortic sinus atherosclerosis...
August 10, 2018: Journal of Biological Chemistry
Ralf Erdmann, Daniel Philipp Schwerter, Immanuel Grimm, Wolfgang Girzalsky
The receptor-cycle of type I peroxisomal matrix protein import is completed by ubiquitination of the membrane-bound receptor Pex5p and its subsequent export back to the cytosol. The receptor export is the only ATP-dependent step of the whole process and is facilitated by two members of the AAA family of proteins (ATPases associated with various cellular activities), namely Pex1p and Pex6p. To gain further insight into substrate recognition by the AAA complex, we generated an N-terminally linked ubiquitin-Pex5p fusion protein...
August 10, 2018: Journal of Biological Chemistry
Lilong Lin, Lining Liang, Xiao Yang, Hao Sun, Yuan Li, Duanqing Pei, Hui Zheng
Bone morphogenetic proteins (BMPs) induce the mesenchymal-epithelial transition (MET) and thereby enhance the generation of induced pluripotent stem cells (iPSCs). However, BMPs are also signaling molecules critical for arresting reprogramming at the pre-iPSC state. In the current study, using mouse embryonic fibroblasts, we found that the time- and concentration-dependent effects of BMPs on reprogramming are mediated by Msh homeobox 2 (MSX2), a homeobox-containing transcription factor. BMPs up-regulated Msx2 by activating SMAD1/5, and MSX2 then directly bound to the promoters and up-regulated the expression of the cadherin 1 ( Cdh1 also known as E-cadherin ), GATA-binding protein 3 ( Gata3 ), and Nanog genes...
August 10, 2018: Journal of Biological Chemistry
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