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  1. Fulltext Subversion of immunoproteasome subunit expression in dengue virus serotype 2-infected HepG2 cells
    Gan CS, Lim PJ, Razif MF, Yusof R, Othman S
    Rev Soc Bras Med Trop, 2017 Jan-Feb;50(1):99-103.
    PMID: 28327809 DOI: 10.1590/0037-8682-0207-2016
    INTRODUCTION:: Infection with all serotypes of dengue virus (DV) results in augmented antigen presentation by MHC class I molecules. However, the upregulation of immunoproteasome subunits only results from infection with two serotypes. This study aims to elucidate changes in the expression of immunoproteasome subunits resulting from infection with DV, particularly DV serotype 2 (DV2).

    METHODS:: HepG2 cells were grown in various culture milieu. Total cellular RNA and proteins were extracted and quantified.

    RESULTS:: Results demonstrated sequestration of immunoproteasome subunits LMP2 and LMP7 in DV2-infected cells.

    CONCLUSIONS:: This study provides insights into the mechanisms underlying immune evasion by DV.
    Matched MeSH terms: Proteasome Endopeptidase Complex/metabolism*
  2. The effect of peptidic and non-peptidic proteasome inhibitors on the biological properties of Acanthamoeba castellanii belonging to the T4 genotype
    Siddiqui R, Saleem S, Khan NA
    Exp Parasitol, 2016 Jun 18;168:16-24.
    PMID: 27327524 DOI: 10.1016/j.exppara.2016.06.006
    The treatment of Acanthamoeba infections remains problematic, suggesting that new targets and/or chemotherapeutic agents are needed. Bioassay-guided screening of drugs that are clinically-approved for non-communicable diseases against opportunistic eukaryotic pathogens is a viable strategy. With known targets and mode of action, such drugs can advance to clinical trials at a faster pace. Recently Bortezomib (proteasome inhibitor) has been approved by FDA in the treatment of multiple myeloma. As proteasomal pathways are well known regulators of a variety of eukaryotic cellular functions, the overall aim of the present study was to study the effects of peptidic and non-peptidic proteasome inhibitors on the biology and pathogenesis of Acanthamoeba castellanii of the T4 genotype, in vitro. Zymographic assays revealed that inhibition of proteasome had detrimental effects on the extracellular proteolytic activities of A. castellanii. Proteasome inhibition affected A. castellanii growth (using amoebistatic assays), but not viability of A. castellanii. Importantly, proteasome inhibitors affected encystation as determined by trophozoite transformation into the cyst form, as well as excystation, as determined by cyst transformation into the trophozoite form. The ability of proteasome inhibitor to block Acanthamoeba differentiation is significant, as it presents a major challenge in the successful treatment of Acanthamoeba infection. As these drugs are used clinically against non-communicable diseases, the findings reported here have the potential to be tested in a clinical setting against amoebic infections.
    Matched MeSH terms: Proteasome Endopeptidase Complex
  3. Peg-4000 increased the mating efficiency of yeast-two hybrid screening process using pmf-box1 as bait
    Nur Athirah Abd Hamid, Ismanizan Ismail
    Sains Malaysiana, 2018;47:2961-2968.
    Protein degradation can occur through Ubiquitin 26S-Proteosome System (UPS). The degradation can be mediated by
    the SCF E3 ubiquitin ligase complex consisting of Skp1, Cullin, and F-box protein as the main components. The F-box
    protein at the C-terminal domain functions to recognize the targeted protein to be ubiquitinated and degraded via UPS.
    A stress-responsive F-box gene, PmF-box1 from Persicaria minor was categorized in the F-box containing kelch repeat
    (FBK) family; a family that specific to plant kingdom. To identify the targeted protein of PmF-box1, yeast-two hybrid system
    (Y2H) was used. In the Y2H screening process, mating efficiency is very important to fish out the interacting proteins.
    Therefore, one modification was conducted to increase the mating efficiency. In this screening, PmF-box1 was used as a
    bait to screen for the Y2H library which was constructed using RNA from plant samples treated with abscisic acid (ABA)
    and polyethylene glycol (PEG)-8000 and control sample. Autoactivation and toxicity tests of bait were performed before
    the Y2H screening. Tests on PmF-box1 showed that it is not toxic to the yeast and cannot autoactivate the yeast reporter
    genes. Mating efficiency was improved from 2.07% to 9.15% after addition of PEG-4000 in the mating culture compared
    to the original protocol, which it also increased the colony number in the screening step afterward. Additionally, bands
    of gene with different sizes were observed on electrophoresis gel after colony PCR analysis from the improved technique.
    Those genes may code for potential interacting proteins that needs further identification and confirmation.
    Matched MeSH terms: Proteasome Endopeptidase Complex
  4. Fulltext Parvimonas micra infection enhances proliferation, wound healing, and inflammation of a colorectal cancer cell line
    Hatta MNA, Mohamad Hanif EA, Chin SF, Low TY, Neoh HM
    Biosci Rep, 2023 Jun 28;43(6).
    PMID: 37218575 DOI: 10.1042/BSR20230609
    The gut microbiota Parvimonas micra has been found to be enriched in gut mucosal tissues and fecal samples of colorectal cancer (CRC) patients compared with non-CRC controls. In the present study, we investigated the tumorigenic potential of P. micra and its regulatory pathways in CRC using HT-29, a low-grade CRC intestinal epithelial cell. For every P. micra-HT-29 interaction assay, HT-29 was co-cultured anaerobically with P. micra at an MOI of 100:1 (bacteria: cells) for 2 h. We found that P. micra increased HT-29 cell proliferation by 38.45% (P=0.008), with the highest wound healing rate at 24 h post-infection (P=0.02). In addition, inflammatory marker expression (IL-5, IL-8, CCL20, and CSF2) was also significantly induced. Shotgun proteomics profiling analysis revealed that P. micra affects the protein expression of HT-29 (157 up-regulated and 214 down-regulated proteins). Up-regulation of PSMB4 protein and its neighbouring subunits revealed association of the ubiquitin-proteasome pathway (UPP) in CRC carcinogenesis; whereas down-regulation of CUL1, YWHAH, and MCM3 signified cell cycle dysregulation. Moreover, 22 clinically relevant epithelial-mesenchymal transition (EMT)-markers were expressed in HT-29 infected with P. micra. Overall, the present study elucidated exacerbated oncogenic properties of P. micra in HT-29 via aberrant cell proliferation, enhanced wound healing, inflammation, up-regulation of UPPs, and activation of EMT pathways.
    Matched MeSH terms: Proteasome Endopeptidase Complex
  5. Fulltext Inhibition of NEDD8 and FAT10 ligase activities through the degrading enzyme NEDD8 ultimate buster 1: A potential anticancer approach
    Tan KL, Pezzella F
    Oncol Lett, 2016 Dec;12(6):4287-4296.
    PMID: 28101194 DOI: 10.3892/ol.2016.5232
    The capabilities of tumour cells to survive through deregulated cell cycles and evade apoptosis are hallmarks of cancer. The ubiquitin-like proteins (UBL) proteasome system is important in regulating cell cycles via signaling proteins. Deregulation of the proteasomal system can lead to uncontrolled cell proliferation. The Skp, Cullin, F-box containing complex (SCF complex) is the predominant E3 ubiquitin ligase, and has diverse substrates. The ubiquitin ligase activity of the SCF complexes requires the conjugation of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to cullin proteins. A tumour suppressor and degrading enzyme named NEDD8 ultimate buster 1 (NUB1) is able to recruit HLA-F-adjacent transcript 10 (FAT10)- and NEDD8-conjugated proteins for proteasomal degradation. Ubiquitination is associated with neddylation and FAT10ylation. Although validating the targets of UBLs, including ubiquitin, NEDD8 and FAT10, is challenging, understanding the biological significance of such substrates is an exciting research prospect. This present review discusses the interplay of these UBLs, as well as highlighting their inhibition through NUB1. Knowledge of the mechanisms by which NUB1 is able to downregulate the ubiquitin cascade via NEDD8 conjugation and the FAT10 pathway is essential. This will provide insights into potential cancer therapy that could be used to selectively suppress cancer growth.
    Matched MeSH terms: Proteasome Endopeptidase Complex
  6. Selective anticancer copper(II)-mixed ligand complexes: targeting of ROS and proteasomes
    Ng CH, Kong SM, Tiong YL, Maah MJ, Sukram N, Ahmad M, et al.
    Metallomics, 2014 Apr;6(4):892-906.
    PMID: 24549332 DOI: 10.1039/c3mt00276d
    Copper compounds can be alternatives to platinum-based anticancer drugs. This study investigated the effects of a series of ternary copper(II) complexes, [Cu(phen)(aa)(H2O)]NO3·xH2O 1-4 (phen = 1,10-phenanthroline; aa = gly (1), DL-ala (2), sar (3), C-dmg (4)), on metastatic and cisplatin-resistant MDA-MB-231 breast cancer cells and MCF10A non-cancerous breast cells, and some aspects of the mechanisms. These complexes were distinctively more antiproliferative towards and induced greater apoptotic cell death in MDA-MB-231 than in MCF10A cells. 2 and 4 could induce cell cycle arrest only in cancer cells. Further evidence from DCFH-DA assay showed higher induction of reactive oxygen species (ROS) in treated cancer cells but minimal ROS increase in normal cells. DNA double-strand breaks, via a γ-H2AX assay, were only detected in cancer cells treated with 5 μM of the complexes. These complexes poorly inhibited chymotrypsin-like activity in the 20S rabbit proteasome while they did not inhibit the three proteolytic sites of MDA-MB-231 cells at 10 μM. However, the complexes could inhibit degradation of ubiquinated proteins of MDA-MB-231 cells. In addition, compound 4 was found to be effective against cervical (Hela), ovarian (SKOV3), lung (A549, PC9), NPC (Hone1, HK1, C666-1), breast (MCF7, T47D), lymphoma and leukemia (Nalmawa, HL60) and colorectal (SW480, SW48, HCT118) cancer cell lines with IC50 values (24 h) in the 1.7-19.0 μM range. Single dose NCI60 screening of 4 showed the complex to be highly cytotoxic to most cancer cell types and more effective than cisplatin.
    Matched MeSH terms: Proteasome Endopeptidase Complex/metabolism
  7. The influenza A virus matrix protein 2 undergoes retrograde transport from the endoplasmic reticulum into the cytoplasm and bypasses cytoplasmic proteasomal degradation
    Bhowmick S, Chakravarty C, Sellathamby S, Lal SK
    Arch Virol, 2017 Apr;162(4):919-929.
    PMID: 27942972 DOI: 10.1007/s00705-016-3153-8
    The matrix protein 2 (M2) is a spliced product of segment 7 genome of influenza A virus. Previous studies indicate its role in uncoating of the viral ribonucleoprotein complex during viral entry and in membrane scission while budding. Despite its crucial role in the viral life cycle, little is known about its subcellular distribution and dynamics. In this study, we have shown that the M2 protein is translocated from the membrane to the cytoplasm by a retrograde route via endosomes and the Golgi network. It utilizes retromer cargo while moving from the endosome to the trans-Golgi network and prevents endosome fusion with the lysosome. Further, M2 interacts with the endoplasmic-reticulum-resident AAA-ATPase p97 for its release into the cytoplasm. Our study also revealed that the M2 protein in the cellular milieu does not undergo ubiquitin-mediated proteasomal degradation. The migration of M2 through this pathway inside the infected cell suggests possible new roles that the M2 protein may have in the host cytoplasm, apart from its previously described functions.
    Matched MeSH terms: Proteasome Endopeptidase Complex/metabolism*
  8. Fulltext The FBXW7-NOTCH interactome: A ubiquitin proteasomal system-induced crosstalk modulating oncogenic transformation in human tissues
    Kar R, Jha SK, Ojha S, Sharma A, Dholpuria S, Raju VSR, et al.
    Cancer Rep (Hoboken), 2021 08;4(4):e1369.
    PMID: 33822486 DOI: 10.1002/cnr2.1369
    BACKGROUND: Ubiquitin ligases or E3 ligases are well programmed to regulate molecular interactions that operate at a post-translational level. Skp, Cullin, F-box containing complex (or SCF complex) is a multidomain E3 ligase known to mediate the degradation of a wide range of proteins through the proteasomal pathway. The three-dimensional domain architecture of SCF family proteins suggests that it operates through a novel and adaptable "super-enzymatic" process that might respond to targeted therapeutic modalities in cancer.

    RECENT FINDINGS: Several F-box containing proteins have been characterized either as tumor suppressors (FBXW8, FBXL3, FBXW8, FBXL3, FBXO1, FBXO4, and FBXO18) or as oncogenes (FBXO5, FBXO9, and SKP2). Besides, F-box members like βTrcP1 and βTrcP2, the ones with context-dependent functionality, have also been studied and reported. FBXW7 is a well-studied F-box protein and is a tumor suppressor. FBXW7 regulates the activity of a range of substrates, such as c-Myc, cyclin E, mTOR, c-Jun, NOTCH, myeloid cell leukemia sequence-1 (MCL1), AURKA, NOTCH through the well-known ubiquitin-proteasome system (UPS)-mediated degradation pathway. NOTCH signaling is a primitive pathway that plays a crucial role in maintaining normal tissue homeostasis. FBXW7 regulates NOTCH protein activity by controlling its half-life, thereby maintaining optimum protein levels in tissue. However, aberrations in the FBXW7 or NOTCH expression levels can lead to poor prognosis and detrimental outcomes in patients. Therefore, the FBXW7-NOTCH axis has been a subject of intense study and research over the years, especially around the interactome's role in driving cancer development and progression. Several studies have reported the effect of FBXW7 and NOTCH mutations on normal tissue behavior. The current review attempts to critically analyze these mutations prognostic value in a wide range of tumors. Furthermore, the review summarizes the recent findings pertaining to the FBXW7 and NOTCH interactome and its involvement in phosphorylation-related events, cell cycle, proliferation, apoptosis, and metastasis.

    CONCLUSION: The review concludes by positioning FBXW7 as an effective diagnostic marker in tumors and by listing out recent advancements made in cancer therapeutics in identifying protocols targeting the FBXW7-NOTCH aberrations in tumors.

    Matched MeSH terms: Proteasome Endopeptidase Complex/metabolism
  9. Different serotypes of dengue viruses differently regulate the expression of the host cell antigen processing machinery
    Gan CS, Yusof R, Othman S
    Acta Trop, 2015 Sep;149:8-14.
    PMID: 25981524 DOI: 10.1016/j.actatropica.2015.05.005
    Dengue virus (DV) infection demonstrates an intriguing virus-induced intracellular membrane alteration that results in the augmentation of major histocompatibility complex (MHC) class I-restricted antigen presentation. As oppose to its biological function in attracting CD8(+) T-cells, this phenomenon appears to facilitate the immune evasion. However, the molecular events that attribute to the dysregulation of the antigen presenting mechanism (APM) by DV remain obscure. In this study, we aimed to characterize the host cell APM upon infection with all serotypes of whole DV. Cellular RNA were isolated from infected cells and the gene expressions of LMP2, LMP7, TAP1, TAP2, TAPBP, CALR, CANX, PDIA3, HLA-A and HLA-B were analyzed via quantitative PCR. The profiles of the gene expression were further validated. We showed that all four DV serotypes modulate host APM at the proteasomal level with DV2 showing the most prominent expression profile.
    Matched MeSH terms: Proteasome Endopeptidase Complex/genetics*
  10. Enantiomeric pair of copper(II) polypyridyl-alanine complexes: Effect of chirality on their interaction with biomolecules
    Ng CH, Chan CW, Lai JW, Ooi IH, Chong KV, Maah MJ, et al.
    J Inorg Biochem, 2016 07;160:1-11.
    PMID: 27105312 DOI: 10.1016/j.jinorgbio.2016.04.003
    Like chiral organic drugs, the chemical and biological properties of metal complexes can be dependent on chirality. Two pairs of [Cu(phen)(ala)(H2O)]X·xH2O (phen=1.10-phenanthroline: X=NO3(-); ala: l-alanine (l-ala), 1 and d-alanine (d-ala) 2; and (X=Cl(-); ala: l-ala, 3 and d-ala, 4) complex salts (x=number of lattice water molecules) have been synthesized and characterized. The crystal structure of 3 has been determined. The same pair of enantiomeric species, viz. [Cu(phen)(l-ala)(H2O)](+) and [Cu(phen)(d-ala)(H2O)](+), have been identified to be present in the aqueous solutions of both 1 and 3, and in those of both 2 and 4 respectively. Both 3 and 4 bind more strongly to ds(AT)6 than ds(CG)6. There is no or insignificant effect of the chirality of 3 and 4 on the production of hydroxyl radicals, binding to deoxyribonucleic acid from calf thymus (CT-DNA), ds(CG)6, G-quadruplex and 17-base pair duplex, and inhibition of both topoisomerase I and proteasome. Among the three proteasome proteolytic sites, the trypsin-like site is inhibited most strongly by these complexes. However, the chirality of 3 and 4 does affect the number of restriction enzymes inhibited, and their binding constants towards ds(AT)6 and serum albumin.
    Matched MeSH terms: Proteasome Endopeptidase Complex/chemistry*
  11. Mucosal responses of brown-marbled grouper Epinephelus fuscoguttatus (Forsskål, 1775) following intraperitoneal infection with Vibrio harveyi
    Chieng CCY, Daud HM, Yusoff FM, Thompson KD, Abdullah M
    J Fish Dis, 2020 Oct;43(10):1249-1258.
    PMID: 32830331 DOI: 10.1111/jfd.13222
    Groupers are popular aquaculture species in South-East Asia, but their cultivation is affected by infectious disease outbreaks. Mucosa-associated lymphoid tissues provide a first-line defence against pathogens; however, few studies are available relating to cellular or proteomic responses of mucosal immunity in grouper. Skin, gill and intestine were sampled from brown-marbled grouper Epinephelus fuscoguttatus (Forsskål, 1775) at 4 and 96 hr post-infection (hpi) and 7 days post-infection (dpi) following intraperitoneal infection with Vibrio harveyi, and stained with haematoxylin/eosin and Alcian Blue/periodic acid-Schiff. Skin mucus was analysed by 2D-gel electrophoresis, and proteins modulated by the bacterial infection identified. In the infected fish, significant increases in sacciform cells in skin and increased levels of nucleoside diphosphate kinase in mucus were detected at 4 hpi. At 96 hpi, goblet cells containing acidic mucins significantly increased in the intestine, while those containing mixed mucins increased in skin and gills of infected fish. Proteasome subunit alpha type-I and extracellular Cu/Zn superoxide dismutase levels also increased in mucus. Rodlet and mast cells did not appear to respond to the infection. Mucosal tissues of grouper appeared actively involved in response to Vibrio infection. This information may help future research on improving grouper health, production and vaccine development.
    Matched MeSH terms: Proteasome Endopeptidase Complex
  12. Fulltext Therapeutic roles of natural remedies in combating hereditary ataxia: A systematic review
    Phang MWL, Lew SY, Chung I, Lim WK, Lim LW, Wong KH
    Chin Med, 2021 Jan 28;16(1):15.
    PMID: 33509239 DOI: 10.1186/s13020-020-00414-x
    BACKGROUND: Hereditary ataxia (HA) represents a group of genetically heterogeneous neurodegenerative diseases caused by dysfunction of the cerebellum or disruption of the connection between the cerebellum and other areas of the central nervous system. Phenotypic manifestation of HA includes unsteadiness of stance and gait, dysarthria, nystagmus, dysmetria and complaints of clumsiness. There are no specific treatments for HA. Management strategies provide supportive treatment to reduce symptoms.

    OBJECTIVES: This systematic review aimed to identify, evaluate and summarise the published literature on the therapeutic roles of natural remedies in the treatment of HA to provide evidence for clinical practice.

    METHODS: A systematic literature search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Web of Science, PubMed and Science Direct Scopus were thoroughly searched for relevant published articles from June 2007 to July 2020.

    RESULTS: Ten pre-clinical and two clinical studies were eligible for inclusion in this systematic review. We identified the therapeutic roles of medicinal plants Brassica napus, Gardenia jasminoides, Gastrodia elata, Ginkgo biloba, Glycyrrhiza inflata, Paeonia lactiflora, Pueraria lobata and Rehmannia glutinosa; herbal formulations Shaoyao Gancao Tang and Zhengan Xifeng Tang; and medicinal mushroom Hericium erinaceus in the treatment of HA. In this review, we evaluated the mode of actions contributing to their therapeutic effects, including activation of the ubiquitin-proteasome system, activation of antioxidant pathways, maintenance of intracellular calcium homeostasis and regulation of chaperones. We also briefly highlighted the integral cellular signalling pathways responsible for orchestrating the mode of actions.

    CONCLUSION: We reviewed the therapeutic roles of natural remedies in improving or halting the progression of HA, which warrant further study for applications into clinical practice.

    Matched MeSH terms: Proteasome Endopeptidase Complex
  13. Fulltext Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53
    Abd-Aziz N, Stanbridge EJ, Shafee N
    J Gen Virol, 2016 Dec;97(12):3174-3182.
    PMID: 27902314 DOI: 10.1099/jgv.0.000623
    Newcastle disease virus (NDV) is a candidate agent for oncolytic virotherapy. Despite its potential, the exact mechanism of its oncolysis is still not known. Recently, we reported that NDV exhibited an increased oncolytic activity in hypoxic cancer cells. These types of cells negatively affect therapeutic outcome by overexpressing pro-survival genes under the control of the hypoxia-inducible factor (HIF). HIF-1 is a heterodimeric transcriptional factor consisting of a regulated α (HIF-1α) and a constitutive β subunit (HIF-1β). To investigate the effects of NDV infection on HIF-1α in cancer cells, the osteosarcoma (Saos-2), breast carcinoma (MCF-7), colon carcinoma (HCT116) and fibrosarcoma (HT1080) cell lines were used in the present study. Data obtained showed that a velogenic NDV infection diminished hypoxia-induced HIF-1α accumulation, leading to a decreased activation of its downstream target gene, carbonic anhydrase 9. This NDV-induced downregulation of HIF-1α occurred post-translationally and was partially abrogated by proteasomal inhibition. The process appeared to be independent of the tumour suppressor protein p53. These data revealed a correlation between NDV infection and HIF-1α downregulation, which highlights NDV as a promising agent to eliminate hypoxic cancer cells.
    Matched MeSH terms: Proteasome Endopeptidase Complex/metabolism*
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