Primary biliary cirrhosis sera recognize not only gp210 but also proteins of the p62 complex bearing N-acetylglucosamine residues from rat liver nuclear envelope

Miyachi, Kiyomitsu; Shibata, Minoru; Onozuka, Yasushi; Kikuchi, Futoshi; Imai, Noriko; Horigome, Tsuneyoshi

doi:10.1007/bf00351173

Cited by 37 publications

(38 citation statements)

References 22 publications

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“…26 Using NPC extracts as the antigen source in immunoblotting assays, the most prominent reactivities had 60 and 200 kd apparent molecular masses, thus suggesting the presence of antibodies directed against the gp210 protein and the nucleoporin p62. 29,31,32 Further, we previously demonstrated that preabsorption of anti-NPC-positive sera with proteins extracted from freshly isolated NPC completely abolished the immunoblotting signal. 14 Similar to what was observed in our previous work, several other bands were detected when anti-NPC-positive sera were tested via immunoblotting; however, these were rare occurences, and their intensities were weaker.…”

Section: Methodsmentioning

confidence: 91%

Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis

et al. 2006

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Although there have been significant advances in understanding the clinical and biochemical features of primary biliary cirrhosis (PBC), there is still a paucity of data on the usefulness of biomarkers as prognostic indicators. This is particularly important at the time of initial diagnosis. Indeed, the widespread use of antimitochondrial antibody testing has led to an earlier diagnosis of asymptomatic PBC and it is difficult to predict which patients will experience a benign versus a rapidly progressive course. To address this issue, we examined a unique population of 127 newly diagnosed patients with PBC during a 15-year period of observation that began in January 1990. Sera from these patients were analyzed for antimitochondrial, antinuclear, and anti-smooth muscle antibodies, and immunoblotting was performed for nuclear pore complex (NPC). The patients were then followed up longitudinally using biochemical liver function tests. No patient was under any medical therapy for PBC at the time of the initial sera collection. Data were analyzed based not only on the clinical features, but also the Mayo score and specific outcome measures, including time to death, need for liver transplantation, and complication free survival. Among patients with early disease, bilirubin increased to >2 mg/dL in the anti-NPC(؉) patients (26% vs. 5%, P ‫؍‬ .019). Anti-NPC antibodies remained stable or slightly increased over the period of observation. In conclusion, anti-NPC identifies patients likely to experience an unfavorable clinical course and more rapid disease progression. (HEPATOLOGY 2006;43:1135-1144

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Section: Methodsmentioning

confidence: 91%

Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis

et al. 2006

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“…Nucleoporin p62 antibodies seem to be characteristic of patients with primary biliary cirrhosis (PBC) (4,10). In addition, four cases of Sjögren syndrome (6) and two cases of systemic lupus erythematosus (4) with p62 antibodies have been described.…”

mentioning

confidence: 99%

Nucleoporin p62 Antibodies in a Case of Mixed Connective Tissue Disease

Kraemer

Kraus

Kneitz

et al. 2003

Clin Vaccine Immunol

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Mixed connective tissue disease is an overlap syndrome characterized by features of different systemic autoimmune diseases and a high titer of U1-snRNP antibodies. We examine here the autoantibodies to nucleoporin p62 in a severe case of mixed connective tissue disease in a young male patient. Thus far, p62 antibodies have mainly been described in cases of primary biliary cirrhosis. We speculate that the presence of p62 antibodies is an indication of a poor prognosis in connective tissue disorders.U1-RNP is a component of the spliceosome complex. Human sera in cases of mixed connective tissue disease (MCTD) recognize the U1-RNA and the U1-specific polypeptides. High anti-U1-RNA titers have been shown to correlate with disease activity (3). Several other antibodies, in addition to the anti-U1-RNP antibodies, have been associated with MCTD (5).During the last 10 years new autoantigens in the nuclear envelope have been characterized. Examples include gp210, lamins, lamin-associated polypeptides, the lamin B receptor, and nucleoporin p62 (7). Nucleoporin p62 has been cloned and sequenced in 1991 (1) and is not identical with p62 characterized by Zhang et al. (11).In the present study we show for the first time nucleoporin p62 antibodies in a young male patient with severe MCTD. The amino acid sequence of nucleoporin p62 contains phenylalanine and glycine (FG)-rich peptide motives, which are binding sites for nuclear transport factors (9). Nucleoporin p62 antibodies seem to be characteristic of patients with primary biliary cirrhosis (PBC) (4, 10). In addition, four cases of Sjögren syndrome (6) and two cases of systemic lupus erythematosus (4) with p62 antibodies have been described.Case report. A 32-year-old male patient was diagnosed with MCTD 7 years previously. His primary manifestations were extremely painful arthralgia and myalgia, Raynaud symptoms, and muscle weakness (accompanied by a pathological pattern in electromyography). Myositis was verified by elevated lactate dehydrogenase, creatinine kinase, and myoglobin levels. Intermittently, pleural effusions and leukopenia were observed. In December 2001 the patient was hospitalized due to very painful myalgia, muscle weakness, and arthralgia. He was nearly unable to walk or move. He reported fatigue and chest pain at deep inspiration. Auscultation revealed percussion dullness and decreased breath sounds over the left lung base. Laboratory parameters showed elevated levels of C-reactive protein (up to 12 mg/dl [0 to 0.5 mg/dl]), fibrinogen (4.7 g/liter [1.8 to 3.5 g/liter]), and immunoglobulin G (IgG; 1,550 mg/dl [690 to 1,400 mg/dl]). Immunologic parameters revealed positive antinuclear antibodies (1:5,120), highly positive anti-RNP, and slightly positive anti-Ro (SS-A). Anti-ds DNS antibodies were occasionally positive. Pulmonary function studies showed restrictive changes of the lung, with a forced vital capacity that was 44% of the predicted value and a diffusing capacity that was 58% of the predicted value. A computed tomographic scan of the chest reveale...

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“…It was shown that 100% of PBC, 70% of RA, and 97% of Sjs sera reacted with some proteins in a rat liver NE fraction. 2 We have reported that some PBC, RA, and Sjs sera react with several GlcNAc-bearing proteins in rat liver NE (27). Thus, we examined the reactivities of PBC, RA, and Sjs sera with Xenopus egg extract proteins and found that these sera react with many proteins in both Xenopus egg membrane and cytosol fractions and inhibit nuclear assembly in a Xenopus egg extract cell free system to various degrees.…”

Section: Analysis Of Proteins Participating In Nuclear Assembly Bymentioning

confidence: 94%

“…Therefore, if we could obtain specific antibodies against these proteins, we would have very powerful tools for analyzing the reaction mechanism. It is known that autoimmune disease sera react with many proteins in the NE (25)(26)(27) and cytosol fractions. We applied such sera to an in vitro Xenopus egg extract nuclear assembly system and found that most sera suppressed the assembly to various extents.…”

Section: The Nuclear Envelope (Ne)mentioning

confidence: 99%

Participation of a Fusogenic Protein, Glyceraldehyde-3-phosphate Dehydrogenase, in Nuclear Membrane Assembly

Nakagawa

Hirano

Inomata

et al. 2003

Journal of Biological Chemistry

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We found an autoimmune serum, K199, that strongly suppresses nuclear membrane assembly in a cell-free system involving a Xenopus egg extract. Four different antibodies that suppress nuclear assembly were affinity-purified from the serum using Xenopus egg cytosol proteins. Three proteins recognized by these antibodies were identified by partial amino acid sequencing to be glyceraldehyde-3-phosphate dehydrogenase (GAPDH), fructose-1,6-bisphosphate aldolase, and the regulator of chromatin condensation 1. GAPDH is known to be a fusogenic protein. To verify the participation of GAPDH in nuclear membrane fusion, authentic antibodies against human and rat GAPDH were applied, and strong suppression of nuclear assembly at the nuclear membrane fusion step was observed. The nuclear assembly activity suppressed by antibodies was recovered on the addition of purified chicken GAPDH. A peptide with the sequence of amino acid residues 70 -94 of GAPDH, which inhibits GAPDH-induced phospholipid vesicle fusion, inhibited nuclear assembly at the nuclear membrane fusion step. We propose that GAPDH plays a crucial role in the membrane fusion step in nuclear assembly in a Xenopus egg extract cell-free system. The nuclear envelope (NE)1 of eukaryotes is composed of inner and outer nuclear membranes, nuclear pore complexes, and the nuclear lamina. NE breakdown during the mitotic prophase results in the dispersal of both nuclear membranes into the mitotic endoplasmic reticulum (ER) network. Inner nuclear membrane proteins such as lamin B receptor, laminaassociated polypeptide 2␤, and emerin reconcentrate on the surface of decondensing chromatin during the late anaphase, and then the NE is re-formed (1, 2). These intrinsic membrane proteins and lamins are believed to play a critical role in NE reassembly (3-5). NE assembly can be studied in vitro using extracts of meiotic or mitotic cells (6, 7). The assembly requires cytosolic factors and is inhibited by a non-hydrolyzable GTP analogue, N-ethylmaleimide, and a calcium chelator, BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid) (8). In vitro, NE assembly is initiated by the binding of membrane vesicles to decondensed chromatin in an energy-independent manner (9 -11). Once bound to chromatin, membrane vesicles fuse and flatten. The insertion of nuclear pore complexes and the expansion of the NE require both energy and cytosolic components (12). The fusion of vesicles on chromatin is inhibited by a non-hydrolyzable GTP analogue (8, 13) and requires Ran GTPase and a regulator of chromatin condensation 1, RCC1/Ran GTP exchange factor (14 -16). Remarkably, agarose beads coated with Ran allow the assembly of a nuclear pore complex-containing NE (17, 18). After the formation of a closed NE around chromatin, further NE growth requires nucleocytoplasmic transport and further membrane fusion (8,19). Analysis of membrane fractions of a Xenopus egg extract suggested that the population of vesicles required for NE assembly is not uniform and that different membranes might be required fo...

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Primary biliary cirrhosis sera recognize not only gp210 but also proteins of the p62 complex bearing N-acetylglucosamine residues from rat liver nuclear envelope

Cited by 37 publications

References 22 publications

Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis

Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis

Nucleoporin p62 Antibodies in a Case of Mixed Connective Tissue Disease

Participation of a Fusogenic Protein, Glyceraldehyde-3-phosphate Dehydrogenase, in Nuclear Membrane Assembly

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