Journal of Biological Chemistry (J BIOL CHEM )

Publisher: American Society of Biological Chemists; Rockefeller Institute for Medical Research; American Society for Biochemistry and Molecular Biology, American Society for Biochemistry and Molecular Biology


Complete content of the Journal of Biological Chemistry as of April 1995.

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    Journal of Biological Chemistry website
  • Other titles
    The Journal of biological chemistry, JBC
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American Society for Biochemistry and Molecular Biology

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    • Authors accepted peer-reviewed manuscript may be posted on an institutional repository
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Proteinuria serves as a direct causative factor of renal tubular cell injury and is highly associated with the progression of chronic kidney disease (CKD) via uncertain mechanisms. Recently, evidence demonstrated that both NLRP3 inflammasome and mitochondria are involved in the CKD progression. The present study was undertaken to examine the role of NLRP3 inflammasome/mitochondria axis in albumin-induced renal tubular injury. In patients with proteinuria, NLRP3 was significantly upregulated in tubular epithelial cells and was positively correlated with the severity of proteinuria. In agreement with these results, albumin remarkably activated NLRP3 inflammasome in both in vitro renal tubular cells and in vivo kidneys in parallel with significant epithelial cell phenotypic alteration and cell apoptosis. Genetic disruption of NLRP3 inflammasome remarkably attenuated albumin-induced cell apoptosis and phenotypic changes under both in vitro and in vivo conditions. In addition, albumin treatment resulted in a significant mitochondrial abnormality as evidenced by the impaired function and morphology, which was markedly reversed by invalidation of NLRP3/caspase-1 signaling pathway. Interestingly, protection of mitochondria function by MnTBAP or CsA robustly attenuated albumin-induced injury in mPTCs. Collectively, these findings demonstrated a pathogenic role of NLRP3 inflammasome/caspase-1/mitochondria axis in mediating albumin-induced renal tubular injury. The discovery of this novel axis provides some potential targets for the treatment of proteinuria-associated renal injury.
    Journal of Biological Chemistry 10/2014;
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    ABSTRACT: GPI-anchored neurotoxin-like receptor binding proteins, such as lynx modulators, are topologically positioned to exert pharmacological effects by binding to the extracellular portion of nAChRs. These actions are generally thought to proceed when both lynx and the nAChRs are on the plasma membrane. Here, we demonstrate that lynx1 also exerts effects on α4β2 nAChRs within the endoplasmic reticulum. Lynx1 affects assembly of nascent α4 and β2 subunits, and alters the stoichiometry of the population that reaches the plasma membrane. Additionally, these data suggest that lynx1 shifts nAChR stoichiometry to low sensitivity (α4)3 (β2)2 pentamers primarily through this interaction in the endoplasmic reticulum, rather than solely via direct modulation of activity on the plasma membrane To our knowledge, these data represent the first test of the hypothesis that a lynx family member, or indeed any GPI-anchored protein, could act within the cell to alter assembly of multi-subunit protein.
    Journal of Biological Chemistry 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian oocytes are surrounded by a highly hydrated hyaluronan (HA)-rich extracellular matrix with embedded cumulus cells, forming the cumulus cell-oocyte complex (COC) matrix. The correct assembly, stability and mechanical properties of this matrix, which are crucial for successful ovulation, transport of the COC to the oviduct and its fertilization, depend on the interaction between HA and specific HA-organizing proteins. Although the proteins inter-αinhibitor (IαI), pentraxin 3 (PTX3) and TNF-stimulated gene-6 (TSG-6) have been identified as being critical for COC matrix formation, its supramolecular organization and the molecular mechanism of COC matrix stabilization remain unknown. Here we used films of end-grafted HA as a model system to investigate the molecular interactions involved in the formation and stabilization of HA matrices containing TSG-6, IαI and PTX3. We found that PTX3 binds neither to HA alone nor to HA films containing TSG-6. This long pentraxin also failed to bind to products of the interaction between IαI, TSG-6 and HA, among which are the covalent HC·HA and HC·TSG-6 complexes, despite the fact that both IαI and TSG-6 are ligands of PTX3. Interestingly, prior encounter with IαI was required for effective incorporation of PTX3 into TSG-6-loaded HA films. Moreover, we demonstrated that this ternary protein mixture made of IαI, PTX3 and TSG-6 is sufficient to promote formation of a stable (i.e. cross-linked) yet highly hydrated HA matrix. We propose that this mechanism is essential for correct assembly of the COC matrix, and may also have general implications in other inflammatory processes that are associated with HA-crosslinking.
    Journal of Biological Chemistry 09/2014;
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    ABSTRACT: The majority of mitochondrial proteins are synthesized with amino-terminal signal sequences. The presequence translocase of the inner membrane (TIM23 complex) mediates the import of these preproteins. The essential TIM23 core complex closely cooperates with partner protein complexes like the import motor PAM and the respiratory chain. The inner mitochondrial membrane also contains a large number of metabolite carriers, yet their association with preprotein translocases has been controversial. We have performed a comprehensive SILAC-based analysis of the TIM23 interactome. Subsequent biochemical studies on identified partner proteins showed that the mitochondrial ADP/ATP carrier (AAC) associates with the membrane-embedded core of the TIM23 complex in a stoichiometric manner, revealing an unexpected connection of mitochondrial protein biogenesis to metabolite transport. Our data indicate that direct TIM23-AAC coupling may support preprotein import into mitochondria when respiratory activity is low.
    Journal of Biological Chemistry 08/2014;
  • Journal of Biological Chemistry 08/2014;
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    ABSTRACT: Bacterial pathogens must adapt/respond rapidly to changing environmental conditions. Bacterial pathogens must adapt/respond rapidly to changing environmental conditions. Ribonucleases (RNases) can be crucial factors contributing to the fast adaptation of RNA levels to different environmental demands. It has been demonstrated that the exoribonuclease polynucleotide phosphorylase (PNPase) facilitates survival of C. jejuni in low temperatures, and favors swimming, chick colonization and cell adhesion/invasion. However, little is known about the mechanism of action of other ribonucleases in this microorganism. Members of the RNB family of enzymes have been shown to be involved in virulence of several pathogens. We have searched C. jejuni genome for homologues and found one candidate that displayed properties more similar to RNase R (Cj-RNR). We show here that Cj-RNR is important for the first steps of infection, the adhesion and invasion of C. jejuni to eukaryotic cells. Moreover, Cj-RNR proved to be active in a wide range of conditions. The results obtained lead us to conclude that Cj-RNR has an important role in the biology of this foodborne pathogen.
    Journal of Biological Chemistry 08/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) are the most potent antigen presenting cells (APCs) in the immune system. DCs present antigens to CD8 and CD4 T cells in the context of class I or II MHC. Recent evidence suggests that autophagy, a conserved intracellular degradation pathway, regulates class II antigen presentation. In vitro studies have shown that deletion of autophagy-related genes reduced antigen presentation by APCs to CD4 T cells. In vivo studies confirmed these findings in the context of infectious diseases. However, the relevance of autophagy-mediated antigen presentation in autoimmunity remains to be elucidated. Here we report that loss of autophagy-related gene 7 (Atg7) in DCs ameliorated experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-mediated mouse model of multiple sclerosis, by reducing in vivo priming of T cells. In contrast, severity of hapten-induced contact hypersensitivity, in which CD8 T cells and NK cells play major roles, was unaffected. Administration of autophagy-lysosomal inhibitor chloroquine, before EAE onset, delayed disease progression, and when administered after the onset, reduced disease severity. Our data show that autophagy is required in DCs for induction of EAE, and suggest that autophagy might be a potential target for treating CD4 T cell-mediated autoimmune conditions.
    Journal of Biological Chemistry 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Placental cell growth depends on an adaptable combination of an endogenous developmental programme and the exogenous influence of maternal growth factors, both of which may be influenced by microRNA (miR)-dependent effects on gene expression. We have previously shown that global miR suppression in placenta accelerates proliferation and enhances levels of growth factor signalling mediators in cytotrophoblast. This study aimed to identify miRs involved in regulating placental growth. An initial array revealed 58 miR species whose expression differs between first trimester, when cytotrophoblast proliferation is rapid, and term, by which time proliferation has slowed. In silico analysis defined potential growth regulatory miRs; amongst these, hsa-miR-145, hsa-miR-377 and hsa-let-7a were predicted to target known placental growth genes, and were higher at term than in first trimester, so were selected for further analysis. Over-expression of miR-377 and Let-7a, but not miR-145, in first trimester placental explants significantly reduced basal cytotrophoblast proliferation and expression of ERK and c-myc. PCR arrays, in-silico analysis, western blotting and 3-UTR luciferase reporter assays revealed targets of miR-145 within the IGF-axis. Analysis of proliferation in placental explants overexpressing miR-145 demonstrated its role as a mediator of IGF-induced trophoblast proliferation. These findings identify miRs 377 and let-7a in regulation of endogenous cell growth and miR-145 in the placental response to maternal stimulation, and will aid the development of therapeutic strategies for problem pregnancies.
    Journal of Biological Chemistry 07/2014;
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    ABSTRACT: The intracellular domains of many ion channels are important for fine tuning their gating kinetics. In Kv11.1 channels, the slow kinetics of channel deactivation, which are critical for their function in the heart, are largely regulated by the N-terminal N-Cap and Per-Arnt-Sim (PAS) domains, as well as the C-terminal cyclic nucleotide-binding homology (cNBH) domain. Here, we use mutant cycle analysis to probe for functional interactions between the N-Cap/PAS domains and the cNBH domain. We identified a specific and stable charge-charge interaction between R56 of the PAS domain and D803 of the cNBH domain, as well an additional interaction between the cNBH domain and the N-Cap, both of which are critical for maintaining slow deactivation kinetics. Furthermore, we found that positively charged arginine residues within the disordered region of the N-Cap interact with negatively charged residues of the C-linker domain. While this interaction is likely more transient than the PAS-cNBD interaction, it is strong enough to stabilize the open conformation of the channel and thus slow deactivation. These findings provide novel insights into the slow deactivation mechanism of Kv11.1 channels.
    Journal of Biological Chemistry 07/2014;
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    ABSTRACT: The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We here investigate the role of Mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of Mst2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the pro-hypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (YAP) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human Mst2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart.
    Journal of Biological Chemistry 07/2014;
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    ABSTRACT: Apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase, plays a key role in the pathogenesis of multiple diseases. Its activity is regulated by thioredoxin (TRX1) but the precise mechanism of this regulation is unclear due to the lack of structural data. Here, we performed biophysical and structural characterization of TRX1-binding domain of ASK1 (ASK1-TBD) and its complex with reduced TRX1. ASK1-TBD is a monomeric and rigid domain which forms a stable complex with reduced TRX1 with 1:1 molar stoichiometry. The binding interaction does not involve the formation of intermolecular disulfide bonds. Residues from the catalytic WCGPC motif of TRX1 are essential for complex stability with W31 being directly involved in the binding interaction as suggested by time-resolved fluorescence. SAXS data reveal a compact and slightly asymmetric shape of ASK1-TBD and suggest reduced TRX1 interacts with this domain through the large binding interface without inducing any dramatic conformational change.
    Journal of Biological Chemistry 07/2014; 289.

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