Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As part of the innate immune defense against HIV infection, OTK18, a zinc finger protein, is upregulated in human macrophages and reduces viral replication through suppression of viral long-terminal repeat promoter activity. Although we know that the processing products of OTK18 accumulate in the cytoplasm of brain perivascular macrophages in advanced HIV encephalitis cases, the molecular mechanisms behind its post-translational processing are still poorly understood. To characterize OTK18 processing, we assessed a panel of protease inhibitors to identify the candidates involved in the OTK18 processing using human monocyte-derived macrophages (MDM) overexpressing OTK18 by recombinant adenoviral gene transfer. Viral infection of MDM strongly increased the processing of OTK18 into its N-terminal fragment. Treatment of OTK18-expressing MDM with calpain and proteasome inhibitors significantly accumulated either full-length or processed OTK18 fragments in time- and dose-dependent manners. A series of OTK18 truncation mutants and synthetic peptides were tested to locate the calpain cleavage sites after arginine 359. Finally, we developed an enhanced cyan and yellow fluorescent protein (ECFP and EYFP)-based intramolecular fluorescent resonance energy transfer (intramolecular FRET) system to monitor the OTK18 endoproteolysis in human microglia cell line. Inhibition of proteasome activity significantly increased the intramolecular FRET signal in the nucleus. These data suggest that calpain and proteasome are involved in OTK18 endoproteolysis and degradation. Additionally, intramolecular FRET has proven to be a useful tool for monitoring the processing in live cells.
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PMID:Calpain and proteasomal regulation of antiretroviral zinc finger protein OTK18 in human macrophages: visualization in live cells by intramolecular FRET. 1903 69

Immunoproteasome induction sustains class 1 antigen presentation and immunological vigilance against HIV-1 in the brain. Investigation of HIV-1-associated alterations in brain protein turnover by the ubiquitin-proteasome system was performed by (1) determining proteasome subunit changes associated with persistent brain inflammation due to HIV-1; (2) determining whether these changes are related to HIV-1 neurocognitive disturbances, encephalitis, and viral loads; and (3) localizing proteasome subunits in brain cells and synapses. On the basis of neurocognitive performance, virological, and immunological measurements obtained within 6 months before death, 153 autopsy cases were selected. Semiquantitative immunoblot analysis performed in the dorsolateral prefrontal cortex revealed up to threefold induction of immunoproteasome subunits LMP7 and PA28alpha in HIV-1-infected subjects and was strongly related to diagnoses of neuropsychological impairment and HIV encephalitis. Low performance on neurocognitive tests specific for dorsolateral prefrontal cortex functioning domains was selectively correlated with immunoproteasome induction. Immunohistochemistry and laser confocal microscopy were then used to localize immunoproteasome subunits to glial and neuronal elements including perikarya, dystrophic axons, and synapses. In addition, HIV loads in brain tissue, cerebrospinal fluid, and blood plasma were robustly correlated to immunoproteasome levels. This persistent "hijacking" of the proteasome by HIV-1-mediated inflammatory response and immunoproteasome induction in the brain is hypothesized to impede turnover of folded proteins in brain cells. This would disrupt neuronal and synaptic protein dynamics, contributing to HIV-1 neurocognitive disturbances.
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PMID:Persistent hijacking of brain proteasomes in HIV-associated dementia. 2003 54