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)

NFB42 (neural F Box 42 kDa) is a novel gene product that is highly enriched in the nervous system. Its predicted protein contains an F box, a motif recently shown to couple cell cycle regulation to the proteasome pathway (Bai, C., Sen, P., Hofmann, K., Ma, L., Goebl, M., Harper, J. W., and Elledge, S. (1996) Cell 86, 263-274). NFB42 mRNA and protein are expressed in all major areas of the adult rat brain but are not detected in non-neural tissues. NFB42 protein is localized primarily to the cytoplasm of neurons and does not appear to be present in glia. The presence of an F box in NFB42 suggests that it may be involved in cell cycle regulation; however, its expression in postmitotic neurons indicates that it is not involved in regulating typical cell cycle events. In an initial attempt to characterize the function of this protein, NFB42 was transfected into N1E-115 neuroblastoma and Chinese hamster ovary cells. The expression of full-length NFB42, but not an F box deletion mutant, inhibits proliferation in both cell lines. Additional experiments demonstrate that NFB42 interacts with Skp1p, a component of the proteasome pathway, and deletion of the F box also inhibits this interaction. Overall, the expression pattern of NFB42, along with the presence of an F box domain and the ability to inhibit growth, suggests that it may play a role in maintaining neurons in a postmitotic state.
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PMID:A novel F box protein, NFB42, is highly enriched in neurons and induces growth arrest. 985 61

F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination and consequent degradation by the proteasome. We have isolated cDNAs encoding a further 10 mammalian F-box proteins. Five of them (FBL3 to FBL7) share structural similarities with Skp2 and contain C-terminal leucine-rich repeats. The other 5 proteins have different putative protein-protein interaction motifs. Specifically, FBS and FBWD4 proteins contain Sec7 and WD40-repeat domains, respectively. The C-terminal region of FBA shares similarity with bacterial protein ApaG while FBG2 shows homology with the F-box protein NFB42. The marked differences in F-box gene expression in human tissues suggest their distinct role in ubiquitin-dependent protein degradation.
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PMID:cDNA cloning and expression analysis of new members of the mammalian F-box protein family. 1094 68

Immunohistochemical data indicate that OCP1 co-localizes exactly with OCP2 in the epithelial gap junction region of the guinea pig organ of Corti (OC). Despite the abundance of OCP1 in the OC, gaining access to its coding sequence -- and, in particular, the 5' end of the coding sequence -- proved unexpectedly challenging. The putative full-length OCP1 cDNA -- 1180 nucleotides in length -- includes a 67 nucleotide 5' leader sequence, 300 codons (including initiation and termination signals), and a 216 nucleotide 3' untranslated region. The cDNA encodes a protein having a predicted molecular weight of 33,700. The inferred amino acid sequence harbors an F-box motif spanning residues 52--91, consistent with a role for OCP1 and OCP2 in the proteasome-mediated degradation of select OC proteins. Although OCP1 displays extensive homology to an F-box protein recently cloned from rat brain (NFB42), clustered sequence non-identities indicate that the two proteins are transcribed from distinct genes. The presumptive human OCP1 gene was identified in the human genome databank. Located on chromosome 1p35, the inferred translation product exhibits 94% identity with the guinea pig OCP1 coding sequence.
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PMID:OCP1, an F-box protein, co-localizes with OCP2/SKP1 in the cochlear epithelial gap junction region. 1147 Jan 90

The ubiquitin-proteasome pathway plays a critical role in the degradation of short-lived and regulatory proteins in a variety of cellular processes. The F-box proteins are part of the ubiquitin-ligase complexes, which mediate ubiquitination and proteasome-dependent degradation of phosphorylated proteins. We previously identified NFB42, an F-box protein that is highly enriched in the nervous system, as a binding partner for the herpes simplex virus 1 UL9 protein, the viral replication-initiator protein, in a yeast two-hybrid screen. In the present work, we find that coexpression of NFB42 and UL9 genes in 293T cells leads to a significant decrease in the level of UL9 protein. Treatment with the 26S-proteasome inhibitor MG132 restores the UL9 protein to normal levels. We have observed also that the UL9 protein is polyubiquitinated in vivo and that the interaction between NFB42 and the UL9 protein is dependent upon phosphorylation of the UL9 protein. These results suggest that the interaction of the UL9 protein with NFB42 results in its polyubiquitination and subsequent degradation by the 26S proteasome. They suggest further a mechanism by which latency of herpes simplex virus 1 can be established in neuronal cells.
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PMID:Replication-initiator protein (UL9) of the herpes simplex virus 1 binds NFB42 and is degraded via the ubiquitin-proteasome pathway. 1290 74

Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCF(NFB42)) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCF(NFB42) mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2alpha induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCF(NFB42) regulates SHPS-1 biosynthesis in response to ER stress.
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PMID:Ubiquitination-mediated regulation of biosynthesis of the adhesion receptor SHPS-1 in response to endoplasmic reticulum stress. 1470 35

Alpha-1 antitrypsin deficiency is the leading cause of childhood liver failure and one of the most common lethal genetic diseases. The disease-causing mutant A1AT-Z fails to fold correctly and accumulates in the endoplasmic reticulum (ER) of the liver, resulting in hepatic fibrosis and hepatocellular carcinoma in a subset of patients. Furthermore, A1AT-Z sequestration in hepatocytes leads to a reduction in A1AT secretion into the serum, causing panacinar emphysema in adults. The purpose of this work was to elucidate the details by which A1AT-Z is degraded in hepatic cell lines. We identified the ubiquitin ligase FBG1, which has been previously shown to degrade proteins by both the ubiquitin proteasome pathway and autophagy, as being key to A1AT-Z degradation. Using chemical and genetic approaches we show that FBG1 degrades A1AT-Z through both the ubiquitin proteasome system and autophagy. Overexpression of FBG1 decreases the half-life of A1AT-Z and knocking down FBG1 in a hepatic cell line, and in mice results in an increase in ATAT. Finally, we show that FBG1 degrades A1AT-Z through a Beclin1-dependent arm of autophagy. In our model, FBG1 acts as a safety ubiquitin ligase, whose function is to re-ubiquitinate ER proteins that have previously undergone de-ubiquitination to ensure they are degraded.
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PMID:FBG1 Is the Final Arbitrator of A1AT-Z Degradation. 2629 39

Epstein-Barr virus (EBV) is a human cancer-related virus closely associated with lymphoid and epithelial malignancies, and EBV glycoprotein B (gB) plays an essential role in viral entry into both B cells and epithelial cells by promoting cell-cell fusion. EBV gB is exclusively modified with high-mannose-linked N-glycans and primarily localizes to the endoplasmic reticulum (ER) with low levels on the plasma membrane (PM). However, the mechanism through which gB is regulated within host cells is largely unknown. Here, we report the identification of F-box only protein 2 (FBXO2), an SCF ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans and attenuates EBV infectivity by targeting N-glycosylated gB for degradation. gB possesses seven N-glycosylation sites, and FBXO2 directly binds to these high-mannose moieties through its sugar-binding domain. The interaction promotes the degradation of glycosylated gB via the ubiquitin-proteasome pathway. Depletion of FBXO2 not only stabilizes gB but also promotes its transport from the ER to the PM, resulting in enhanced membrane fusion and viral entry. FBXO2 is expressed in epithelial cells but not B cells, and EBV infection up-regulates FBXO2 levels. In summary, our findings highlight the significance of high-mannose modification of gB and reveal a novel host defense mechanism involving glycoprotein homeostasis regulation.
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PMID:Epstein-Barr virus activates F-box protein FBXO2 to limit viral infectivity by targeting glycoprotein B for degradation. 3005 82