BackgroundLow Density Lipoprotein (LDL) hypercholesterolemia, and its associated cardiovascular diseases, are some of the leading causes of death worldwide. The ability of proprotein convertase subtilisin/kexin 9 (PCSK9) to modulate circulating LDL cholesterol (LDLc) concentrations made it a very attractive target for LDLc management. To date, the most advanced approaches for PCSK9 inhibition are monoclonal antibody (mAb) therapies. Although shown to lower LDLc significantly, mAbs face functional limitations because of their relatively short in vivo half-lives necessitating frequent administration. Here, we evaluated the long-term efficacy and safety of PCSK9-specific active vaccines in different preclinical models.Methods and FindingPCSK9 peptide-based vaccines were successfully selected by our proprietary technology. To test their efficacy, wild-type (wt) mice, Ldlr +/− mice, and rats were immunized with highly immunogenic vaccine candidates. Vaccines induced generation of high-affine PCSK9-specific antibodies in all species. Group mean total cholesterol (TC) concentration was reduced by up to 30%, and LDLc up to 50% in treated animals. Moreover, the PCSK9 vaccine-induced humoral immune response persisted for up to one year in mice, and reduced cholesterol levels significantly throughout the study. Finally, the vaccines were well tolerated in all species tested.ConclusionsPeptide-based anti-PCSK9 vaccines induce the generation of antibodies that are persistent, high-affine, and functional for up to one year. They are powerful and safe tools for long-term LDLc management, and thus may represent a novel therapeutic approach for the prevention and/or treatment of LDL hypercholesterolemia-related cardiovascular diseases in humans.
Rho GTPases regulate diverse cellular functions including adhesion, cytokinesis and motility, as well as the activity of the transcription factors NF-jB, serum response factor and C/EBP. a-Catulin, an a-catenin-related protein that shares structural similarities with cytoskeletal linker proteins, facilitates Rho signalling by serving as a scaffold for the Rho-specific guanine nucleotide exchange factor Lbc. We report here that a-catulin also interacts with a key component of the NF-jB signalling pathway, namely the IjB kinase (IKK)-b. In co-immunoprecipitations, a-catulin can bind IKK-b and Lbc. Ectopic expression of a-catulin augmented NF-jB activity, promoted cell migration and increased resistance to apoptosis, whereas knockdown experiments showed the opposite effects. Together, these features suggest that a-catulin has tumorigenic potential.
XIAP is known as a potent inhibitor of apoptosis, but in addition is involved in cellular signalling, including the NFκB, JNK and TGFβ pathways. Our search for XIAP-interacting partners led us to Siva1, a proapoptotic protein that is known to play a role in T-cell apoptosis through a caspase-dependent mitochondrial pathway. The interaction sites between XIAP and Siva1 were mapped to the RING domain of XIAP and the N-terminal, SAH-containing and death-homology-region-containing domains of Siva1. Co-immunoprecipitation experiments showed that XIAP, Siva1 and TAK1 form a ternary complex in Jurkat T cells. Reporter-gene analysis revealed that Siva1 inhibits XIAP- and TAK1-TAB1-mediated NFκB activation. By contrast, Siva1 increased XIAP- and TNFα-mediated AP1 activity and prolonged TNFα-induced JNK activation, whereas knock down of Siva1 resulted in reduced JNK activation. This suggests that Siva1 differentially modulates signalling by JNK and NFκB and shifts the balance between these pathways towards enhanced JNK activation, a situation that promotes apoptosis. Ectopically expressed Siva1 increased caspase-3 activity, which was inhibited by XIAP in a ubiquitin-ligase-dependent manner. In line with this, Siva1 was lysine-48-linked polyubiquitylated by XIAP. Our findings suggest that, via physical interaction with XIAP and TAK1, Siva1 diminishes NFκB and enhances JNK activity to favour apoptosis.
Major receptor group common cold virus HRV89 was adapted to grow in HEp-2 cells, which are permissive for minor group human rhinoviruses (HRVs) but which only marginally support growth of major-group viruses. After 32 blind passages in these cells, each alternating with boosts of the recovered virus in HeLa cells, HRV89 acquired the capacity to effectively replicate in HEp-2 cells, attaining virus titers comparable to those in HeLa cells although no cytopathic effect was observed. Several clones were isolated and shown to replicate in HeLa cells whose ICAM-1 was blocked with monoclonal antibody R6.5 and in COS-7 cells, which are devoid of ICAM-1. Blocking experiments with recombinant very-low-density lipoprotein receptor fragments and enzyme-linked immunosorbent assays indicated that the mutants bound a receptor different from that used by minor-group viruses. Determination of the genomic RNA sequence encoding the capsid protein region revealed no changes in amino acid residues at positions equivalent to those involved in the interaction of HRV14 or HRV16 with ICAM-1. One mutation was within the footprint of a very-low-density lipoprotein receptor fragment bound to minor-group virus HRV2. Since ICAM-1 not only functions as a vehicle for cell entry but has also a "catalytic" function in uncoating, the use of other receptors must have important consequences for the entry pathway and demonstrates the plasticity of these viruses.Human rhinoviruses (HRVs), a major cause of mild upper respiratory infections generally recognized as common colds, are small icosahedral particles with a capsid composed of four viral proteins, VP1 through VP4 (for a review see reference 9). The capsid encases a genomic RNA of about 7,500 nucleotides encoding a polyprotein which is cotranslationally and autocatalytically processed by three viral proteinases, P2A, P3C, and P3CD (the precursor of P3C). A final maturation cleavage of VP0 to VP2 and VP4 occurs concomitantly with encapsidation by an as yet unidentified protease. With one exception (HRV87), the serotypes can be divided into a major group, using intercellular adhesion molecule 1 (ICAM-1) as the viral receptor, and a minor group, attaching to the cell via members of the low-density lipoprotein receptor (LDLR) family including LDLR, the very-low-density lipoprotein receptor (VLDLR), and LDLR-related protein (LRP) (16,27). The nature of the HRV87 receptor is unknown (50). Whereas major-group viruses are highly specific for human ICAM-1 and fail to attach to the homologue of other species, minor-group viruses bind to a variety of LDLRs, most likely due to the high evolutionary conservation of these membrane proteins. Replication usually does not occur in nonhuman cells even when suitable receptors are present, and adaptation of HRV2 to growth in mouse cells has been shown to be correlated with mutations in nonstructural proteins P2B and P2C (23).As HRVs of both receptor groups are very similar with respect to the amino acid sequence and the three-dimensional structure of the viral cap...
We describe here the identification and initial characterization of a novel human gene termed IKIP (I kappa B kinase interacting protein) that is located on chromosome 12 in close proximity to APAF1 (apoptotic protease-activating factor-1). IKIP and APAF1 share a common 488 bp promoter from which the two genes are transcribed in opposite directions. Three IKIP transcripts are generated by differential splicing and alternative exon usage that do not show significant homology to other genes in the databases. Similar to APAF1, expression of IKIP is enhanced by X-irradiation, and both genes are dependent on p53. Moreover, IKIP promotes apoptosis when transfected into endothelial cells. We conclude that IKIP is a novel p53 target gene with proapoptotic function.
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