Antinuclear Autoantibodies: Fluorescent Highlights on Structure and Function in the Nucleus

Hemmerich, Peter; Mikecz, Anna von

doi:10.1159/000024420

Cited by 7 publications

(2 citation statements)

References 145 publications

(109 reference statements)

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“…Autoantibodies that recognize intracellular nucleoprotein complexes such as nucleosomes, spliceosomal components, and nucleolus-associated proteins (reviewed in Tan, 1989;Hemmerich and von Mikecz, 2000) represent a hallmark of systemic rheumatic diseases. The factors triggering the formation of autoreactive B cells against nuclear proteins are still unknown, but genetic, hormonal, and environmental components are involved.…”

Section: Introductionmentioning

confidence: 99%

Subcellular Recruitment of Fibrillarin to Nucleoplasmic Proteasomes: Implications for Processing of a Nucleolar Autoantigen

Chen

Rockel

Steinweger

et al. 2002

MBoC

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A prerequisite for proteins to interact in a cell is that they are present in the same intracellular compartment. Although it is generally accepted that proteasomes occur in both, the cytoplasm and the nucleus, research has been focusing on cytoplasmic protein breakdown and antigen processing, respectively. Thus, little is known on the functional organization of the proteasome in the nucleus. Here we report that within the nucleus 20S and 26S proteasomes occur throughout the nucleoplasm and partially colocalize with splicing factor-containing speckles. Because proteasomes are absent from the nucleolus, a recruitment system was used to analyze the molecular fate of nucleolar protein fibrillarin: Subtoxic concentrations of mercuric chloride (HgCl 2 ) induce subcellular redistribution of fibrillarin and substantial colocalization (33%) with nucleoplasmic proteasomes in different cell lines and in primary cells isolated from mercury-treated mice. Accumulation of fibrillarin and fibrillarin-ubiquitin conjugates in lactacystin-treated cells suggests that proteasome-dependent processing of this autoantigen occurs upon mercury induction. The latter observation might constitute the cell biological basis of autoimmune responses that specifically target fibrillarin in mercury-mouse models and scleroderma. INTRODUCTIONThe bulk of nonlysosomal proteolysis is carried out by the ATP-powered 26S proteasome, which is involved in the regulation of major cellular processes such as progression of the cell cycle, transcription, flux of substrates through metabolic pathways, elimination of abnormal proteins, and antigen processing (Hershko and Ciechanover, 1998;Kloetzel, 2001). In most cultured mammalian cells 80 -90% of the protein breakdown occurs by the proteasome pathway (Lee and Goldberg, 1998). The 26S proteasome is composed of two distinct subcomplexes: the central 20S proteasome, in which proteins are degraded, and two flanking 19S complexes, which provide substrate specificity and regulation. The 20S proteasome forms the core subunit harboring multiple catalytic centers located within the hollow cavity of a cylinder (Finley, 2002). This topology sequesters the catalytic sites from potential substrates (Voges et al., 1999). Most of the substrates of the eukaryotic 26S proteasome must be marked by ubiquitination in order to be destroyed. This involves the covalent attachment of multiple ubiquitin molecules to the target protein (Ciechanover, 1998). However, exceptions to the rule such as ornithine decarboxylase (ODC), which is degraded by the 26S proteasome without ubiquitinylation are known, and more are currently under investigation (Murakami et al., 1992;Verma and Deshaies, 2000).Proteasomes generate oligopeptides, most of which are further degraded by distinct endopeptidases and aminopeptidases into amino acids. However, a fraction of these peptides escape complete destruction and are subjected to antigen presentation. The peptides are transported to the endoplasmic reticulum via the transporter associated with antigen pre...

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Section: Introductionmentioning

confidence: 99%

Subcellular Recruitment of Fibrillarin to Nucleoplasmic Proteasomes: Implications for Processing of a Nucleolar Autoantigen

Chen

Rockel

Steinweger

et al. 2002

MBoC

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“…The current cell biological knowledge on the structure and function of subnuclear compartments as targets of ANA is summarized by Hemmerich and von Mikecz [24]. The authors emphasize that new techniques, such as confocal laser scanning microscopy, fluorescence resonance energy transfer and in vivo observation of cellular events, provide new possibilities to study targets of ANA specificities with respect to subnuclear architecture and function.…”

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confidence: 99%

Editorial Overview: Antinuclear Antibody- and Extractable Nuclear Antigen-Related Diseases

Hiepe

Dörner

Burmester³

2000

Int Arch Allergy Immunol

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In 1948, the observation of the LE cell phenomenon in a patient with systemic lupus erythematosus (SLE) began the discovery of a broad variety of autoantibodies directed to nuclear antigens called antinuclear antibodies (ANA). Nowadays, different ANA serve as important diagnostic parameters for differentiating most of the connective tissue diseases, such as SLE, neonatal lupus syndromes, Sjögren’s syndrome, scleroderma, autoimmune myositis, mixed connective tissue disease and other overlaps. This overview summarizes the history of ANA and their detection methods, in part to introduce the subsequent papers dealing with special topics of ANA-related diseases in this issue. Furthermore, the pathogenic role of these autoantibodies in targeting non-organ-specific intracellular antigens as a functional important constituent of a subcellular particle or multimolecular complex is addressed. Notably, some of these autoantibodies have functioned as significant tools for cell biologists to elucidate the subcellular structures and functions of these autoantigens. In the future, we can expect further advances to answer such important questions as why these antigens are targets of autoantibodies, what is their pathogenic impact and what are the triggers of autoimmunity?

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Antinuclear Autoantibodies in Cutaneous Lupus Erythematosus: Biochemical and Cell Biological Characterization of Ro/SSA

Mikecz¹

2005

Cutaneous Lupus Erythematosus

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Antinuclear Autoantibodies: Fluorescent Highlights on Structure and Function in the Nucleus

Cited by 7 publications

References 145 publications

Subcellular Recruitment of Fibrillarin to Nucleoplasmic Proteasomes: Implications for Processing of a Nucleolar Autoantigen

Subcellular Recruitment of Fibrillarin to Nucleoplasmic Proteasomes: Implications for Processing of a Nucleolar Autoantigen

Editorial Overview: Antinuclear Antibody- and Extractable Nuclear Antigen-Related Diseases

Antinuclear Autoantibodies in Cutaneous Lupus Erythematosus: Biochemical and Cell Biological Characterization of Ro/SSA

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