ABSTRACT The major enzyme system catalysing the degradation of intracellular proteins is the proteasome system. A central inner chamber of the cylinder-shaped 20 S proteasome contains the active site, formed by N-terminal threonine residues. The 20 S proteasomes are extremely inefficient in degrading folded protein substrates and therefore one or two multisubunit 19 S regulatory particles bind to one or both ends of the 20 S proteasome cylinder, forming 26 S and 30 S proteasomes respectively. These regulatory complexes are able to bind proteins marked as proteasome substrates by prior conjugation with polyubiquitin chains, and initiate their unfolding and translocation into the proteolytic chamber of the 20 S proteasome, where they are broken down into peptides of 3-25 amino acids. The polyubiquitin tag is removed from the substrate protein by the deubiquitinating activity of the 19 S regulator complex. Under conditions of an intensified immune response, many eukaryotic cells adapt by replacing standard 20 S proteasomes with immuno-proteasomes and/or generating the proteasome activator complex, PA28. Both of these adaptations change the protein-breakdown process for optimized generation of antigenic peptide epitopes that are presented by the class I MHCs. Hybrid proteasomes (19 S regulator-20 S proteasome-PA28) may have a special function during the immune response. The functions of other proteasome accessory complexes, such as PA200 and PI31 are still under investigation.
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ABSTRACT: Many diseases are transmitted by mosquitoes, including malaria, dengue fever, yellow fever, filariasis, and West Nile fever. Chemical control plays a major role in managing mosquito-borne diseases. However, excessive and continuous application of insecticides has caused the development of insecticide resistance in many species including mosquito, and this has become the major obstacle to controlling mosquito-borne diseases. Insecticide resistance is the result of complex polygenic inheritance, and the mechanisms are not well understood. Ribosomal protein RPS29 was found to be associated with DM resistance in our previous study. In this study, we aim to further investigate the involvement of RPS29 in deltamethrin resistance. In this study, tandem affinity purification was used to identify proteins that can interact with RPS29. Among the candidate proteins, CYP6N3, a member of the CYP450 superfamily, was identified, and binding to RPS29 was confirmed in vitro and in vivo by GST pull-down and immunofluorescence. CCK-8 assay was used to investigate the RPS29-CTP6N3 interaction in relation to DM resistance. CYP6N3 overexpression significantly enhanced DM resistance and insect cell viability, but this was reversed by RPS29 overexpression. Western blot was used to study the mechanism of interaction between RPS29 and CYP6N3. RPS29 increases CYP6N3 protein degradation through the proteasome. These observations indicate that CYP6N3, a novel RPS29-interacting partner, could stimulate deltamethrin resistance in mosquito cells and RPS29 overexpression targeted CYP6N3 for proteosomal degradation, abrogating the CYP6N3-associated resistence to deltamethrin. Our findings provide a novel mechanism associated with CYP450s mediated DM resistance.PLoS ONE 04/2014; 9(4):e94611. DOI:10.1371/journal.pone.0094611 · 3.53 Impact Factor
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ABSTRACT: Improved methods for integrated analysis of heterogeneous large-scale omic data are direly needed. Here, we take a network-based approach to this challenge. Given two networks, representing different types of gene interactions, we construct a map of linked modules, where modules are genes strongly connected in the first network and links represent strong inter-module connections in the second. We develop novel algorithms that considerably outperform prior art on simulated and real data from three distinct domains. First, by analyzing protein-protein interactions and negative genetic interactions in yeast, we discover epistatic relations among protein complexes. Second, we analyze protein-protein interactions and DNA damage-specific positive genetic interactions in yeast and reveal functional rewiring among protein complexes, suggesting novel mechanisms of DNA damage response. Finally, using transcriptomes of non-small-cell lung cancer patients, we analyze networks of global co-expression and disease-dependent differential co-expression and identify a sharp drop in correlation between two modules of immune activation processes, with possible microRNA control. Our study demonstrates that module maps are a powerful tool for deeper analysis of heterogeneous high-throughput omic data.Nucleic Acids Research 02/2014; DOI:10.1093/nar/gku102 · 8.81 Impact Factor
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ABSTRACT: A novel approach to the development of a precise method of intraoperative diagnostics of thyroid cancer has been proposed on the basis of fundamental study of proteasomes in malignant tumors of mammals and human. The method is based on estimation of proteasome activity in small fragments of the tumor and adjacent tissues.Biology Bulletin 07/2014; 41(4):318-323. DOI:10.1134/S1062359014040104 · 0.24 Impact Factor