Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin E3 ligases are important cellular components for endoplasmic reticulum (ER)-associated degradation due to their role in substrate-specific ubiquitination, which is required for retrotranslocation (dislocation) of most unwanted proteins from the ER to the cytosol for proteasome degradation. However, our understanding of the molecular mechanisms of how E3 ligases confer substrate-specific recognition, and their role in substrate retrotranslocation is limited especially in mammalian cells. mK3 is a type III ER membrane protein encoded by murine gamma herpesvirus 68. As conferred by its N-terminal RING-CH domain, mK3 has E3 ubiquitin ligase activity. In its role as an immune evasion protein, mK3 specifically targets nascent major histocompatibility complex class I heavy chains (HC) for rapid degradation. The mechanism by which mK3 extracts HC from the ER membrane into the cytosol for proteasome-mediated degradation is unknown. Evidence is presented here that HC down-regulation by mK3 is dependent on the p97 AAA-ATPase. By contrast, the kK5 protein of Kaposi's sarcoma-associated herpesvirus is p97-independent despite the fact that it is highly homologous to mK3. mK3 protein was also found in physical association with Derlin1, an ER protein recently implicated in the retrotranslocation of HC by immune evasion protein US11, but not US2, of human cytomegalovirus. The mechanistic implications of these findings are discussed.
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PMID:The viral E3 ubiquitin ligase mK3 uses the Derlin/p97 endoplasmic reticulum-associated degradation pathway to mediate down-regulation of major histocompatibility complex class I proteins. 1644 59

Relatively small genomes and high replication rates allow viruses and bacteria to accumulate mutations. This continuously presents the host immune system with new challenges. On the other side of the trenches, an increasingly well-adjusted host immune response, shaped by coevolutionary history, makes a pathogen's life a rather complicated endeavor. It is, therefore, no surprise that pathogens either escape detection or modulate the host immune response, often by redirecting normal cellular pathways to their advantage. For the purpose of this chapter, we focus mainly on the manipulation of the class I and class II major histocompatibility complex (MHC) antigen presentation pathways and the ubiquitin (Ub)-proteasome system by both viral and bacterial pathogens. First, we describe the general features of antigen presentation pathways and the Ub-proteasome system and then address how they are manipulated by pathogens. We discuss the many human cytomegalovirus (HCMV)-encoded immunomodulatory genes that interfere with antigen presentation (immunoevasins) and focus on the HCMV immunoevasins US2 and US11, which induce the degradation of class I MHC heavy chains by the proteasome by catalyzing their export from the endoplasmic reticulum (ER)-membrane into the cytosol, a process termed ER dislocation. US2- and US11-mediated subversion of ER dislocation ensures proteasomal degradation of class I MHC molecules and presumably allows HCMV to avoid recognition by cytotoxic T cells, whilst providing insight into general aspects of ER-associated degradation (ERAD) which is used by eukaryotic cells to purge their ER of defective proteins. We discuss the similarities and differences between the distinct pathways co-opted by US2 and US11 for dislocation and degradation of human class I MHC molecules and also a putatively distinct pathway utilized by the murine herpes virus (MHV)-68 mK3 immunoevasin for ER dislocation of murine class I MHC. We speculate on the implications of the three pathogen-exploited dislocation pathways to cellular ER quality control. Moreover, we discuss the ubiquitin (Ub)-proteasome system and its position at the core of antigen presentation as proteolysis and intracellular trafficking rely heavily on Ub-dependent processes. We add a few examples of manipulation of the Ub-proteasome system by pathogens in the context of the immune system and such diverse aspects of the host-pathogen relationship as virus budding, bacterial chromosome integration, and programmed cell death, to name a few. Finally, we speculate on newly found pathogen-encoded deubiquitinating enzymes (DUBs) and their putative roles in modulation of host-pathogen interactions.
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PMID:Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions. 1714 6

Polypeptides are organized into distinct substructures, termed protein domains, that are often associated with diverse functions. These modular units can act as binding sites, areas of post-translational modification, and sites of complex multimerization. The human cytomegalovirus US2 gene product is organized into discrete domains that together catalyze the proteasome-dependent degradation of class I major histocompatibility complex heavy chains. US2 co-opts the endogenous ER quality control pathway in order to dispose of class I. The US2 endoplasmic reticulum (ER)-lumenal region is the class I binding domain, whereas the carboxyl terminus can be referred to as the degradation domain. In the present study, we examined the role of the US2 transmembrane domain in virus-mediated class I degradation. Replacement of the US2 transmembrane domain with that of the CD4 glycoprotein completely blocked the ability of US2 to induce class I destruction. A more precise mutagenesis revealed that subregions of the US2 transmembrane domain differ in their ability to trigger class I degradation. Collectively, the data support a model in which US2-mediated class I degradation occurs as a highly regulated process where the US2 transmembrane domain and cytoplasmic tail work in concert to eliminate class I molecules. Host factors, including a signal peptidase complex, probably associate with the US2 molecule in a coordinated fashion to create a predislocation complex to promote the extraction of class I out of the ER. The results imply that the ER quality control machinery may recognize and eliminate misfolded proteins using a similar multistep regulated process.
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PMID:A bipartite trigger for dislocation directs the proteasomal degradation of an endoplasmic reticulum membrane glycoprotein. 1808 79

Inhibition of cell-surface expression of major histocompatibility complex class I molecules by human cytomegalovirus (HCMV, a beta-herpesvirus) promotes escape from recognition by CD8+ cytotoxic T cells. The HCMV US2 and US11 gene products induce class I downregulation during the early phase of HCMV infection by facilitating the degradation of class I heavy chains. The HCMV proteins promote the transport of the class I heavy chains across the endoplasmic reticulum (ER) membrane into the cytosol by a process referred to as 'dislocation', which is then followed by proteasome degradation. This process has striking similarities to the degradation of misfolded ER proteins mediated by ER quality control. Even though the major steps of the dislocation reaction have been characterized, the cellular proteins, specifically the ER chaperones involved in targeting class I for dislocation, have not been fully delineated. To elucidate the chaperones involved in HCMV-mediated class I dislocation, we utilized a chimeric class I heavy chain with an affinity tag at its carboxy terminus. Interestingly, US2 but not US11 continued to target the class I chimera for destruction, suggesting a structural limitation for US11-mediated degradation. Association studies in US2 cells and in cells that express a US2 mutant, US2-186HA, revealed that class I specifically interacts with calnexin, BiP and calreticulin. These findings demonstrate that US2-mediated class I destruction utilizes specific chaperones to facilitate class I dislocation. The data suggest a more general model in which the chaperones that mediate protein folding may also function during ER quality control to eliminate aberrant ER proteins.
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PMID:Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules. 1842 Jul 89

Throughout the course of natural evolution with its host, the human cytomegalovirus (HCMV) has developed a variety of strategies to avoid immune recognition and clearance. The major histocompatibility complex (MHC) class I antigen presentation pathway is a major target of the virus. HCMV encodes at least six gene products that modulate the processing of endoplasmic reticulum (ER)-resident MHC class I molecules. Here, we show that two virus-encoded proteins, US2 and US3, coordinate their functions toward the common goal of attenuating class I protein surface expression. In cells stably expressing both US2 and US3, class I molecules were almost completely downregulated from the cell surface. In addition, pulse-chase analysis revealed that the proteasome-dependent turnover of class I molecules occurs more rapidly in cells expressing both US2 and US3 than either US2 or US3 alone. The ability of US3 to retain class I molecules in the ER produces a target-rich environment for US2 to mediate the destruction of class I heavy chains. In fact, expression of US3 enhanced the association between US2 and class I molecules, thus encouraging their dislocation and degradation. This immune evasion strategy ensures that viral antigens are not presented on the cell surface during the early phase of HCMV infection, a critical time of replication and viral proliferation.
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PMID:Human cytomegalovirus-encoded immune modulators partner to downregulate major histocompatibility complex class I molecules. 1900 44

The human cytomegalovirus proteins US2 and US11 have co-opted endoplasmic reticulum (ER) quality control to facilitate the destruction of major histocompatibility complex class I heavy chains. The class I heavy chains are dislocated from the ER to the cytosol, where they are deglycosylated and subsequently degraded by the proteasome. We examined the role of TRAM1 (translocating chain-associated membrane protein-1) in the dislocation of class I molecules using US2- and US11-expressing cells. TRAM1 is an ER protein initially characterized for its role in processing nascent polypeptides. Co-immunoprecipitation studies demonstrated that TRAM1 can complex with the wild type US2 and US11 proteins as well as deglycosylated and polyubiquitinated class I degradation intermediates. In studies using US2- and US11-TRAM1 knockdown cells, we observed an increase in levels of class I heavy chains. Strikingly, increased levels of glycosylated heavy chains were observed in TRAM1 knockdown cells when compared with control cells in a pulse-chase experiment. In fact, US11-mediated class I dislocation was more sensitive to the lack of TRAM1 than US2. These results provide further evidence that these viral proteins may utilize distinct complexes to facilitate class I dislocation. For example, US11-mediated class I heavy chain degradation requires Derlin-1 and SEL1L, whereas signal peptide peptidase is critical for US2-induced class I destabilization. In addition, TRAM1 can complex with the dislocation factors Derlin-1 and signal peptide peptidase. Collectively, the data support a model in which TRAM1 functions as a cofactor to promote efficient US2- and US11-dependent dislocation of major histocompatibility complex class I heavy chains.
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PMID:TRAM1 participates in human cytomegalovirus US2- and US11-mediated dislocation of an endoplasmic reticulum membrane glycoprotein. 1912 97

The US2 and US11 gene products of human cytomegalovirus promote viral evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US2 and US11 initiate dislocation of newly translocated major histocompatibility complex class I (MHC I) from the ER to the cytosol for proteasome-mediated degradation, thereby decreasing cell surface MHC I. Despite being instrumental in elucidating the mammalian ERAD pathway, the responsible E3 ligase or ligases remain unknown. Using a functional small interfering RNA library screen, we now identify TRC8 (translocation in renal carcinoma, chromosome 8 gene), an ER-resident E3 ligase previously implicated as a hereditary kidney cancer gene, as required for US2-mediated MHC I ubiquitination. Depletion of TRC8 prevents MHC I ubiquitination and dislocation by US2 and restores cell surface MHC I. TRC8 forms an integral part of a novel multiprotein ER complex that contains MHC I, US2, and signal peptide peptidase. Our data show that the TRC8 E3 ligase is required for MHC I dislocation from the ER and identify a new complex associated with mammalian ERAD.
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PMID:The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER. 1972 Aug 73

Signal peptide-dependent insertion of newly synthesized proteins into the endoplasmic reticulum (ER) is a multi-step process, whose fidelity varies with the identity of the protein and the cell type. ER translocation of prions is sensitive to conditions of acute ER stress in a manner that pre-emptively prevents their aggregation and proteo-toxicity. While this has been documented for extreme ER stress conditions and for a special type of proteins, the impact of chronic ER stress on protein translocation in general has not been well characterized. The unfolded protein response (UPR) is a cytoprotective signaling pathway activated by ER stress. The transcription factor X-box-binding protein 1 (XBP-1) is a key element of the mammalian UPR, which is activated in response to ER stress. Deletion of XBP-1 generates constitutive chronic ER stress conditions. Chronic ER stress can also be produced pharmacologically, for example by prolonged treatment with proteasome inhibitors, which abrogates XBP-1 activation. We tested the impact of chronic ER stress on protein insertion into the ER with special emphasis on antibody secreting cells (ASCs), as these cells cope physiologically with prolonged stress conditions. We show that XBP-1 in plasmablasts and fibroblasts controls the ER translocation of US2, a viral-encoded protein with a priori poor insertion efficiency. Using monoclonal antibodies that preferentially recognize ER-mis-inserted micro Ig chains we demonstrate that prolonged treatment of plasmablasts with proteasome inhibitors, as well as deletion of XBP-1, impaired the translocation of mu chains to the ER. Our data suggest that ASCs under prolonged ER stress conditions endure cytoplasmic mislocalization of Ig proteins. This mislocalization may further explain the exquisite sensitivity of multiple myeloma to proteasome inhibitors.
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PMID:Prolonged endoplasmic reticulum stress promotes mislocalization of immunoglobulins to the cytoplasm. 2035 76

Human cytomegalovirus (HCMV), a member of the Herpesviridae family, is proficient at establishing lifelong persistence within the host in part due to immune modulating genes that limit immune recognition. HCMV encodes at least five glycoproteins within its unique short (US) genomic region that interfere with MHC class I antigen presentation, thus hindering viral clearance by cytotoxic T lymphocytes (CTL). Specifically, US3 retains class I within the endoplasmic reticulum (ER), while US2 and US11 induce class I heavy chain destruction. A cooperative effect on class I down-regulation during stable expression of HCMV US2 and US3 has been established. To address the impact of US3 on US11-mediated MHC class I down-regulation, the fate of class I molecules was examined in US3/US11-expressing cells and virus infection studies. Co-expression of US3 and US11 resulted in a decrease of surface expression of class I molecules. However, the class I molecules in US3/US11 cells were mostly retained in the ER with an attenuated rate of proteasome destruction. Analysis of class I levels from virus-infected cells using HCMV variants either expressing US3 or US11 revealed efficient surface class I down-regulation upon expression of both viral proteins. Cells infected with both US3 and US11 expressing viruses demonstrate enhanced retention of MHC class I complexes within the ER. Collectively, the data suggests a paradigm where HCMV-induced surface class I down-regulation occurs by diverse mechanisms dependent on the expression of specific US genes. These results validate the commitment of HCMV to limiting the surface expression of class I levels during infection.
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PMID:Human cytomegalovirus US3 modulates destruction of MHC class I molecules. 2249 7

Misfolded endoplasmic reticulum (ER) proteins are dislocated towards the cytosol and degraded by the ubiquitin-proteasome system in a process called ER-associated protein degradation (ERAD). During infection with human cytomegalovirus (HCMV), the viral US2 protein targets HLA class I molecules (HLA-I) for degradation via ERAD to avoid elimination by the immune system. US2-mediated degradation of HLA-I serves as a paradigm of ERAD and has facilitated the identification of TRC8 (also known as RNF139) as an E3 ubiquitin ligase. No specific E2 enzymes had previously been described for cooperation with TRC8. In this study, we used a lentiviral CRISPR/Cas9 library targeting all known human E2 enzymes to assess their involvement in US2-mediated HLA-I downregulation. We identified multiple E2 enzymes involved in this process, of which UBE2G2 was crucial for the degradation of various immunoreceptors. UBE2J2, on the other hand, counteracted US2-induced ERAD by downregulating TRC8 expression. These findings indicate the complexity of cellular quality control mechanisms, which are elegantly exploited by HCMV to elude the immune system.
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PMID:Multiple E2 ubiquitin-conjugating enzymes regulate human cytomegalovirus US2-mediated immunoreceptor downregulation. 2874 40


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