Respiratory syncytial virus (RSV) infection causes bronchiolitis and pneumonia in infants.RSV has a linear single-stranded RNA genome encoding 11 proteins, 2 of which are nonstructural (NS1 and NS2). RSV specifically downregulates STAT2 protein expression, thus enabling the virus to evade the host type I interferon response. Degradation of STAT2 requires proteasomal activity and is dependent on the expression of RSV NS1 and NS2 (NS1/2). Here we investigate whether RSV NS proteins can assemble ubiquitin ligase (E3) enzymes to target STAT2 to the proteasome. We demonstrate that NS1 contains elongin C and cullin 2 binding consensus sequences and can interact with elongin C and cullin 2 in vitro; therefore, NS1 has the potential to act as an E3 ligase. By knocking down expression of specific endogenous E3 ligase components using small interfering RNA, NS1/2, or RSV-induced STAT2, degradation is prevented. These results indicate that E3 ligase activity is crucial for the ability of RSV to degrade STAT2. These data may provide the basis for therapeutic intervention against RSV and/or logically designed live attenuated RSV vaccines.Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants and young children (28,31). RSV belongs to the genus Pneumovirus in the subfamily Pneumovirinae of the family Paramyxoviridae. It is an enveloped, nonsegmented negative-strand RNA virus encoding 11 proteins, including nucleocapsid proteins (N, P, and L), surface proteins (F and G), and a matrix protein (M). In addition, the genome encodes two nonstructural proteins (NS1 and NS2), the functions of which are less clearly defined. RSV primarily infects epithelial cells of the respiratory tract and replicates exclusively in the cytoplasm. Progeny RSV particles exit the host cell by budding through the apical surfaces of polarized cells (35).In order to combat such infections, the immune system has evolved a potent antiviral response. Mediators, known as the type I interferons (alpha interferon [IFN-␣] and IFN-), stimulate the production of a range of antiviral gene products that limit virus replication and spread (4, 22). The type I IFN receptor consists of two subunits, IFNAR1 and IFNAR2, which are associated with the Janus kinases JAK1 and TYK2, respectively (23). Activation of these receptor tyrosine kinases results in tyrosine phosphorylation of signal transducer and activator of transcription 2 (STAT2) and STAT1. Activated STAT2 and STAT1 associate with interferon regulatory factor 9 (IRF-9) to form the transcriptional activator complex interferon-stimulated gene factor 3 (ISGF-3). These complexes translocate to the nucleus and bind IFN-stimulated response elements (ISRE) to initiate gene transcription and therefore antiviral immunity (8).Wild-type RSV induces a weak type I IFN response following infection (27), suggesting that it has the capacity to evade this host defense mechanism in order to establish a successful infection. RSV is thought to block IFN-␣ and - signaling...
Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)-and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.Cytokines such as interleukin-2 (IL-2) regulate the immune response via interaction with cell surface receptors on target cells. These receptors interact with cytoplasmic tyrosine kinases, specifically, members of the Janus kinase (JAK) family, which subsequently phosphorylate signal transducer and activator of transcription (STAT) proteins. Phosphorylation of STATs results in their dimerization and translocation to the nucleus and subsequent transcriptional activation of genes important for proliferation and differentiation (11). Inhibition of these signaling pathways is crucial for the control of the inflammatory response (16). The suppressors of cytokine signaling (SOCS/SSI/CIS) are thought to play a key role in this process and are upregulated by and inhibit the JAK/STAT pathway in a classic negative-feedback manner (7,32,39). Eight SOCS family proteins have been described, CIS (cytokine-inducible SH2 domain-containing protein) and SOCS1 to SOCS7 (10,22,29). These proteins are characterized by two common structural motifs, an SH2 domain and a C-terminal SOCS box. The SOCS box is thought to interact with elongin B/C, part of an E3 ubiquitin ligase complex that targets associated proteins for degradation through the ubiquitin pathway (27). As well as SOCS, a number of other protein subfamilies including the von Hippel-Lindau (VHL) tumor suppressor protein contain this SOCS box motif, indicating that it may have an important and conserved role (17). The SOCS box of VHL associates with an E3 ligase complex and induces the proteasomal degradation of hypoxia-inducible factor 1␣ (40).More recently, Asb, an adipocyte-specific ankyrin and SOCS box-containing protein, has been shown to interact with the adaptor protein APS (adapter protein with PH and SH2 domain) to enable recruitment of elongin B/C to the insulin receptor (43).SOCS1 and SOCS3 are induced ra...
Context. Observations of the γ-ray sky with Fermi led to significant advances towards understanding blazars, the most extreme class of active galactic nuclei. A large fraction of the population detected by Fermi is formed by BL Lacertae (BL Lac) objects, whose sample has always suffered from a severe redshift incompleteness due to the quasi-featureless optical spectra. Aims. Our goal is to provide a significant increase of the number of confirmed high-redshift BL Lac objects contained in the 2 LAC Fermi/LAT cataloge. Methods. For 103 Fermi/LAT blazars, photometric redshifts using spectral energy distribution fitting have been obtained. The photometry includes 13 broad-band filters from the far ultraviolet to the near-IR observed with Swift/UVOT and the multi-channel imager GROND at the MPG/ESO 2.2 m telescope. Data have been taken quasi-simultaneously and the remaining source-intrinsic variability has been corrected for. Results. We release the UV-to-near-IR 13-band photometry for all 103 sources and provide redshift constraints for 75 sources without previously known redshift. Out of those, eight have reliable photometric redshifts at z > ∼ 1.3, while for the other 67 sources we provide upper limits. Six of the former eight are BL Lac objects, which quadruples the sample of confirmed high-redshift BL Lac. This includes three sources with redshifts higher than the previous record for BL Lac, including CRATES J0402-2615, with the best-fit solution at z ≈ 1.9.
The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyperphosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity. IntroductionThe somatic valine-to-phenylalanine (V617F) mutation in JAK2 has been associated with a variety of myeloproliferative disorders (MPD), including polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF). [1][2][3][4][5] In wild-type JAKs the JH2 domain inhibits the JH1 kinase domain through interactions at 2 interfaces, with the region containing V617 being predicted to preserve the inactive conformation of the activation loop. 6 The V617F mutation might alter this conformation and perhaps stabilize the activation loop in an active state, or it may prevent access of other proteins to the catalytic domain. The V617 residue of JAK2 is conserved in the JH2 domain of JAK1 and TYK2, whereas in JAK3 it is replaced by methionine. Like JAK2 V617F, analogous mutations in JAK1 or TYK2 also results in their constitutive activation. 7 Janus kinases require the JH2 pseudokinase domain for normal physiologic activation of the JH1 catalytic domain. Therefore, it seems that the V617F mutation may disrupt the putative inhibition of the catalytic domain by the pseudokinase domain and create a constitutively activated kinase. However, the Janus kinases are also potently regulated by the suppressor of cytokine signaling (SOCS) proteins that are thought to bind to the JH1 catalytic loop and target the kinases for degradation. Whether SOCS can regulate the JAK2 V617F mutant has not been explored. 8 SOCS1 and SOCS3 bind to the catalytic groove of JAK2 via their kinase inhibitory region (KIR) to inhibit catalytic activity. 8 Both of these SOCS proteins can also target TEL-JAK2 and wild-type JAK2 for ubiquitination and degradation via their SOCS box ECS ubiquitin E3 ligase interaction motif. 9,10 A...
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