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Biochimica Et Biophysica Acta 2010Genuine La proteins contain two RNA binding motifs, a La motif (LAM) followed by a RNA recognition motif (RRM), arranged in a unique way to bind RNA. These proteins... (Review)
Review
Genuine La proteins contain two RNA binding motifs, a La motif (LAM) followed by a RNA recognition motif (RRM), arranged in a unique way to bind RNA. These proteins interact with an extensive variety of cellular RNAs and exhibit activities in two broad categories: i) to promote the metabolism of nascent pol III transcripts, including precursor-tRNAs, by binding to their common, UUU-3'OH containing ends, and ii) to modulate the translation of certain mRNAs involving an unknown binding mechanism. Characterization of several La-RNA crystal structures as well as biochemical studies reveal insight into their unique two-motif domain architecture and how the LAM recognizes UUU-3'OH while the RRM binds other parts of a pre-tRNA. Recent studies of members of distinct families of conserved La-related proteins (LARPs) indicate that some of these harbor activity related to genuine La proteins, suggesting that their UUU-3'OH binding mode has been appropriated for the assembly and regulation of a specific snRNP (e.g., 7SK snRNP assembly by hLARP7/PIP7S). Analyses of other LARP family members suggest more diverged RNA binding modes and specialization for cytoplasmic mRNA-related functions. Thus it appears that while genuine La proteins exhibit broad general involvement in both snRNA-related and mRNA-related functions, different LARP families may have evolved specialized activities in either snRNA or mRNA-related functions. In this review, we summarize recent progress that has led to greater understanding of the structure and function of La proteins and their roles in tRNA processing and RNP assembly dynamics, as well as progress on the different LARPs.
Topics: Amino Acid Sequence; Animals; Autoantigens; Binding Sites; Conserved Sequence; Fungal Proteins; Humans; Models, Molecular; Molecular Sequence Data; Protein Structure, Tertiary; RNA; RNA Processing, Post-Transcriptional; Ribonucleoproteins; Sequence Homology, Amino Acid; SS-B Antigen
PubMed: 20138158
DOI: 10.1016/j.bbagrm.2010.01.011 -
Arthritis and Rheumatism Jul 2002
Topics: Animals; Apoptosis; Autoantigens; Autoimmunity; Cell Death; Humans
PubMed: 12124851
DOI: 10.1002/art.10415 -
European Journal of Immunology Mar 2007Positional cloning of the underlying genes for the rare syndrome autoimmune polyendocrinopathy candidadiasis extrodermal dystrophy (APECED) opened a new venue of... (Review)
Review
Positional cloning of the underlying genes for the rare syndrome autoimmune polyendocrinopathy candidadiasis extrodermal dystrophy (APECED) opened a new venue of research on the role of central tolerance in autoimmunity. The associated autoimmune regulator gene (AIRE), was found to be expressed in medullary thymus epithelial cells (mTEC) in both man and mice, and to control promiscuous expression of sets of self antigens. The lack of AIRE in both mice and man led to the development of a quite specific, but also an inter-individual variable, set of autoimmune and infectious diseases. An article in this issue of the European Journal of Immunology demonstrates that several autoantigens controlled by AIRE are variably expressed in different human individuals. Most importantly it is shown that carriers of the type 1 diabetes (T1D) associated locus IDDM2 show lower expression of insulin in mTEC, as controlled by AIRE. The genetic variability of autoantigen expression in the thymus thus seems to determine the variable predisposition to autoimmunity.
Topics: Animals; Antigenic Variation; Autoantigens; Humans; Immune Tolerance; Transcription Factors; AIRE Protein
PubMed: 17323409
DOI: 10.1002/eji.200737152 -
Clinical and Experimental Immunology May 2011The sulphilimine cross-link of the Goodpasture (GP) autoantigen is a novel molecular mechanism (structural constraint) for conferring immune privilege to a site which... (Review)
Review
The sulphilimine cross-link of the Goodpasture (GP) autoantigen is a novel molecular mechanism (structural constraint) for conferring immune privilege to a site which otherwise is susceptible to structural changes that induce an immunogenic and pathogenic conformation. Perturbation of the assembly or cleavage of the sulphilimine cross-links could be a key factor in the aetiology of Goodpasture's disease in susceptible individuals.
Topics: Anti-Glomerular Basement Membrane Disease; Autoantigens; Collagen Type IV; Cross-Linking Reagents; Epitopes, B-Lymphocyte; Epitopes, T-Lymphocyte; Humans; Protein Conformation
PubMed: 21447121
DOI: 10.1111/j.1365-2249.2011.04356.x -
Molecular Metabolism Oct 2021Since its discovery 100 years ago, insulin, as the 'cure' for type 1 diabetes, has rescued the lives of countless individuals. As the century unfolded and the autoimmune... (Review)
Review
BACKGROUND
Since its discovery 100 years ago, insulin, as the 'cure' for type 1 diabetes, has rescued the lives of countless individuals. As the century unfolded and the autoimmune nature of type 1 diabetes was recognised, a darker side of insulin emerged. Autoimmunity to insulin was found to be an early marker of risk for type 1 diabetes in young children. In humans, it remains unclear if autoimmunity to insulin is primarily due to a defect in the beta cell itself or to dysregulated immune activation. Conversely, it may be secondary to beta-cell damage from an environmental agent (e.g., virus). Nevertheless, direct, interventional studies in non-obese diabetic (NOD) mouse models of type 1 diabetes point to a critical role for (pro)insulin as a primary autoantigen that drives beta cell pathology.
SCOPE OF REVIEW
Modelled on Koch's postulates for the pathogenicity of an infectious agent, evidence for a pathogenic role of (pro)insulin as an autoantigen in type 1 diabetes, particularly applicable to the NOD mouse model, is reviewed. Evidence in humans remains circumstantial. Additionally, as (pro)insulin is a target of autoimmunity in type 1 diabetes, its application as a therapeutic tool to elicit antigen-specific immune tolerance is assessed.
MAJOR CONCLUSIONS
Paradoxically, insulin is both a 'cure' and a potential 'cause' of type 1 diabetes, actively participating as an autoantigen to drive autoimmune destruction of beta cells - the instrument of its own destruction.
Topics: Animals; Autoantibodies; Autoantigens; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Insulin; Insulin-Secreting Cells; Mice; Mice, Inbred NOD
PubMed: 34242821
DOI: 10.1016/j.molmet.2021.101288 -
BMC Genomics Jul 2011Autoantibodies against self-antigens have been associated not only with autoimmune diseases, but also with cancer and are even found in healthy individuals. The...
BACKGROUND
Autoantibodies against self-antigens have been associated not only with autoimmune diseases, but also with cancer and are even found in healthy individuals. The mechanism causing the autoantibody response remains elusive for the majority of the immunogenic antigens. To deepen the understanding of autoantibody responses, we ask whether natural-occurring, autoimmunity-associated and tumor-associated antigens have structural or biological features related to the immune response. To this end, we have carried out the most comprehensive in-silicio study of different groups of autoantigens including large antigen sets identified by our groups combined with publicly available antigen sets.
RESULTS
We found evidence for an enrichment of genes with a larger exon length increasing the probability of the occurrence of potential immunogenic features such as mutations, SNPs, immunogenic sequence patterns and structural epitopes, or alternative splicing events. While SNPs seem to play a more central role in autoimmunity, somatic mutations seem to be stronger enriched in tumor-associated antigens. In addition, antigens of autoimmune diseases are different from other antigen sets in that they appear preferentially secreted, have frequently an extracellular location, and they are enriched in pathways associated with the immune system. Furthermore, for autoantibodies in general, we found enrichment of sequence-based properties including coiled-coils motifs, ELR motifs, and Zinc finger DNA-binding motifs. Moreover, we found enrichment of proteins binding to proteins or nucleic acids including RNA and enrichment of proteins that are part of ribosome or spliceosome. Both, homologies to proteins of other species and an enrichment of ancient protein domains indicate that immunogenic proteins are evolutionary conserved and that mimicry might play a central role.
CONCLUSIONS
Our results provide evidence that proteins which i) are evolutionary conserved, ii) show specific sequence motifs, and iii) are part of cellular structures show an increased likelihood to become autoimmunogenic.
Topics: Amino Acid Motifs; Autoantigens; Databases, Genetic; Exons; Molecular Mimicry; Nucleic Acids; Polymorphism, Single Nucleotide; Protein Binding; Protein Interaction Domains and Motifs; Zinc Fingers
PubMed: 21726451
DOI: 10.1186/1471-2164-12-340 -
Annual Review of Immunology May 2016Systemic autoimmune diseases are characterized by specific targeting of a limited group of ubiquitously expressed autoantigens by the immune system. This review examines... (Review)
Review
Systemic autoimmune diseases are characterized by specific targeting of a limited group of ubiquitously expressed autoantigens by the immune system. This review examines the mechanisms underlying their selection as immune targets. Initiation of autoimmune responses likely reflects the presentation of antigens with a distinct structure not previously encountered by the immune system, in a proimmune context (injury, malignancy, or infection). Causes of modified structure include somatic mutation and posttranslational modifications (including citrullination and proteolysis). Many autoantigens are components of multimolecular complexes, and some of the other components may provide adjuvant activity. Propagation of autoimmune responses appears to reflect a bidirectional interaction between the immune response and the target tissues in a mutually reinforcing cycle: Immune effector pathways generate additional autoantigen, which feeds further immune response. We propose that this resonance may be a critical principle underlying disease propagation, with specific autoantigens functioning as the hubs around which amplification occurs.
Topics: Adjuvants, Immunologic; Animals; Autoantigens; Autoimmune Diseases; Autoimmunity; Feedback, Physiological; Humans; Immune Tolerance; Immunodominant Epitopes; Multiprotein Complexes; Rheumatic Diseases; Structure-Activity Relationship
PubMed: 26907212
DOI: 10.1146/annurev-immunol-032414-112205 -
Cold Spring Harbor Perspectives in... Aug 2012Islet autoantigens associated with autoimmune type 1 diabetes (T1D) are expressed in pancreatic β cells, although many show wider patterns of expression in the... (Review)
Review
Islet autoantigens associated with autoimmune type 1 diabetes (T1D) are expressed in pancreatic β cells, although many show wider patterns of expression in the neuroendocrine system. Within pancreatic β cells, every T1D autoantigen is in one way or another linked to the secretory pathway. Together, these autoantigens play diverse roles in glucose regulation, metabolism of biogenic amines, as well as the regulation, formation, and packaging of secretory granules. The mechanism(s) by which immune tolerance to islet-cell antigens is lost during the development of T1D, remains unclear. Antigenic peptide creation for immune presentation may potentially link to the secretory biology of β cells in a number of ways, including proteasomal digestion of misfolded products, exocytosis and endocytosis of cell-surface products, or antigen release from dying β cells during normal or pathological turnover. In this context, we evaluate the biochemical nature and immunogenicity of the major autoantigens in T1D including (pro)insulin, GAD65, ZnT8, IA2, and ICA69.
Topics: Animals; Autoantigens; Cation Transport Proteins; Diabetes Mellitus, Type 1; Disease Models, Animal; Glutamate Decarboxylase; Homeodomain Proteins; Humans; Insulin; Insulin-Secreting Cells; Mice; Proteostasis Deficiencies; Receptor-Like Protein Tyrosine Phosphatases, Class 8; Secretory Vesicles; Short Stature Homeobox Protein; Zinc Transporter 8
PubMed: 22908193
DOI: 10.1101/cshperspect.a007658 -
Blood Mar 1991
Topics: Amino Acid Sequence; Autoantigens; Base Sequence; Gene Amplification; Granulomatosis with Polyangiitis; Humans; Leukemia; Molecular Sequence Data
PubMed: 2001463
DOI: No ID Found -
Immunologic Research Mar 2013Autoreactive CD4 T cells play a central role in the development of type 1 diabetes. The BDC panel of diabetogenic T cell clones was originally isolated from non-obese... (Review)
Review
Autoreactive CD4 T cells play a central role in the development of type 1 diabetes. The BDC panel of diabetogenic T cell clones was originally isolated from non-obese diabetic mice and has been used to study the role of autoreactive CD4 T cells and T cell autoantigens in the development of diabetes. Recent studies by our group have led to the identification of two new target antigens for clones of this panel. This review describes the proteomic strategy used for antigen identification, the antigens identified, and the potential contribution of post-translational modification to autoantigen generation. In addition, we compare peptide epitopes for the T cell clones and discuss their potential applications in investigating the role of T cell autoantigens in the pathogenesis and regulation of disease.
Topics: Animals; Autoantigens; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Humans; Proteomics
PubMed: 22971988
DOI: 10.1007/s12026-012-8375-6