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FARE2015 WINNERS Sorted by Study Section FARE2015 WINNERS Sorted By Study Section Biochemistry - Proteins Andrezza Campos-Chagas Visiting Fellow NIAID Sicpin, the first immunomodulatory salivary protein described in black flies significantly reduced T and B cell proliferation and directly binds to soluble CD4 receptor Hematophagy is key to blood feeding arthropods reproductive success and an important link in pathogen transmission cycles. Salivary gland homogenates from blackflies have been shown to contain immunomodulatory activity on murine splenocytes. However, the molecule(s) responsible for this salivary activity remains elusive thus far. Here, we report the first immunosuppressive protein from blackfly salivary glands. Sicpin (Simulium cell proliferation inhibitor) was produced in E. coli and purified using size exclusion and ion exchange chromatography. Purified Sicpin was LPS-decontaminated and its sequence verified by N-terminal sequencing and LC-MS/MS analysis. Sicpin inhibited cell proliferation in a dose-response manner independently of the mitogen utilized (ConA, LPS, CD3/CD28 and Pokeweed). LPS or ConA stimulated cells had a significant lower proliferation rates (P<0.001) in the presence of Sicpin (IC50=0.5uM) with 10uM completely abrogating cell proliferation. Flow cytometry analysis showed that Sicpin inhibited proliferation of CD19+ B-cells and CD4+/CD8+ T-cells. Sicpin did not induce apoptosis or necrosis in mitogen-induced proliferative responses by murine splenocytes as determined by flow cytometry. Sicpin also inhibits antigen-specific cell proliferation without inducing apoptosis in resting or mitogen-induced splenocytes. We demonstrate that the production IFN-alpha, IL4, IL5, IL6 and IL10 by splenocytes stimulated by ConA or LPS was dose-dependently reduced by Sicpin. Reduction of cytokines in presence of Sicpin could lead to a retardation of B and T cell activity. Carrageenan-induced paw-edema model showed that the intensity of edema significantly decreases when Sicpin was administered at 5 and 15 ug/animal. The molecular mechanism of Sicpin on cell proliferation inhibition is currently under investigation; however, initial binding experiments using SPR analysis showed a direct binding to soluble CD4 receptor with a calculated KD of 17.77 nM. Direct binding of Sicpin to CD4 could inhibit the subsequent TCR ligation-induced T cell signaling at the earliest steps including tyrosine phosphorylation of the receptors, downstream effector proteins, and lipid raft reorganization. The immune suppressive and anti-inflammatory properties of Sicpin should be explored as a strategy to modulate immune responses in infection and tumor proliferation as well as its involvement in parasite transmission Biochemistry - Proteins Dongying Ma Visiting Fellow NIAID Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat Since the early 1930s, it has been reported that the saliva of vampire bats exhibits anticoagulant properties. However, the identity of the saliva anticoagulant remained elusive for the past 80 years. Here we have finally identified the coagulation inhibitor from the salivary gland of the bat Desmodus rotundus, which is designated as Desmolaris. Desmolaris is a novel 21.5-kDa naturally deleted (Kunitz 1- domainless) form of human tissue factor pathway inhibitor (TFPI). Recombinant Desmolaris was expressed in HEK293 cells and characterized as a slow, tight, and noncompetitive inhibitor of FXIa by a mechanism modulated by heparin (KD in pM range). Desmolaris also inhibits FXa with lower affinity, independently of protein S. In addition, Desmolaris binds kallikrein and reduces bradykinin generation in plasma activated with kaolin. Comparison the activities of truncated- and mutated (R32L)-forms of Desmolaris determined that Arg32 in the Kunitz-1 domain is critical for protease inhibition. Moreover, Kunitz-2 and the C-terminus domains mediate interaction of Desmolaris with heparin and are required for optimal inhibition of FXIa and FXa. Notably, Desmolaris (100 µg/kg) inhibited FeCl3-induced carotid artery thrombus without prolonging bleeding time and reduced collagen/epinephrine mediated thromboembolism in mice. Desmolaris also reduced the polyphosphate (polyP)-induced vascular permeability and blocked the inflammatory effects of FXa in vivo. The results elucidate that Desmolaris is the anti-hemostatic and anti-inflammatory molecule which is helpful to fulfill the blood sucking process of vampire bat. In the future, Desmolaris could potentially be used as an anticoagulant or as a template for the development of new therapies to prevent and treat thrombosis. Desmolaris is fast- acting and effective at lower concentrations. In addition, Desmolaris does not promote bleeding at concentrations needed to prevent clots formation in mice suggests that Desmolaris-based therapies may be safer than current clinical anticoagulant drugs, which carry side effects of bleeding. Biochemistry - Proteins Yi-Han Lin Postdoctoral Fellow NICHD Exploitation of the host cell lipidation machinery by the Legionella pneumophilla U-box E3 ligase GobX Upon infection, bacterial pathogens release effector proteins into host cells to support their intracellular replication. Knowing the function and host target of those bacterial effector proteins is a key step to uncover bacterial pathogenesis in general, and for therapeutic advancement to emerge. Legionella pneumophilla, the causative agent of Legionnaire’s disease, represents an ideal model organism to study bacterial effector proteins. L. pneumophilla translocates over 300 effector proteins into host cells during infection. Most effector proteins have no known functions due to lack of primary sequence homology. We used a bioinformatics approach (HHpred) that identifies remote protein homologies to search for L. pneumophilla effector proteins that contain E3 ubiquitin ligase domains. Mimicking E3 ubiquitin ligases to hijack the host ubiquitination pathway is a strategy many bacteria use during infection, but only 1 L. pneumophilla effector has been confirmed to be an E3 ligase. We identified 17 additional L. pneumophilla effectors of unknown function as putative E3 ligases, 5 of which we confirmed experimentally in vitro or in vivo. Among them, GobX, a 209-amino acid (aa) effector protein, contains a U-box E3 ligase domain within aa51-100. Interestingly, in transiently transfected COS-1 cells, GobX showed intense localization to the Golgi compartment depending on the region between aa161- 200. Site-directed mutagenesis identified that Cys175 and its neighboring residues are critical for Golgi localization, and their substitution with alanine either completely abolished or strongly reduced GobX localization to the Golgi. Biochemical analyses using the metabolic labeling agent 17-ODYA followed by click chemistry revealed that GobX is S-palmitoylated on Cys175. Transfection of HEK293T cells with GobX and 23 mammalian DHHC acyl transferases indicated that GobX is preferentially palmitoylated by DHHC12, 20, 21, 22, and 23. Our study represents the first example of a Legionella pneumophilla effector protein that utilizes host-mediated palmitoylation for its subcellular localization. It also shows that E3 ligases are more abundant in bacterial pathogens than predicted, and that GobX can simultaneously exploit two host machineries, ubiquitination and lipidation. Biochemistry - Proteins Thuy-Ai Nguyen Postdoctoral Fellow NIEHS The p53 protein interactome is also a p53-regulated cistrome The p53 tumor suppressor is a transcription factor that regulates the expression of cell cycle, DNA repair, apoptosis and many other genes in response to cellular stress. While activated p53 directly binds genes and alters expression, the effects of cancer drugs on promoter selectivity, transcription regulation, and protein-protein interactions with p53 are poorly understood. We are elucidating the human p53 network by examining p53 binding, induced gene expression and protein interactors under diverse stress conditions. Combining p53 immunoprecipitation, SILAC (stable isotope labeling with amino acids in cell culture) and mass spectrometry, we have identified 45 novel p53 protein interactors in response to the chemotherapeutic drug Doxorubicin. Functional annotation of this interactome reveals proteins that participate in RNA binding, mitochondria, transcription and cellular metabolism. Remarkably, when we compared the list of p53 interactors with our p53 ChIP-seq and microarray studies, we found that p53 bound the promoters of 97% of these interactors. Additionally, the interactors all have at least one p53 target response element near their transcription start sites. Furthermore, over 30% of the interactors were differentially expressed in response to p53 activating drugs based on microarray analyses. We are currently validating whether the p53 interactome is also a p53-regulated cistrome using ChIP-qPCR to examine binding and qPCR to examine induced gene expression. While p53 is known to participate in several autoregulatory feedback loops, most of which act through Mdm2, we have uncovered what appears to be 44 new loops in the p53 regulatory network. This unexpected finding could be due to our examination of the p53 interactome in response to stress, whereas previous p53 mass spec studies were restricted to p53 overexpression in p53 null cells in the absence of stress signals. In its role as guardian of the genome, p53 may have numerous feedback loops to connect it with various stress and signal transduction
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