Introduction

Doctor to Lady Macbeth: This disease is beyond my practice… I think, but dare not speak.

Lady Macbeth: Hell is murky.

- Act V, scene I. Macbeth, by William Shakespeare.

Understanding the role of aminoacyl-tRNA synthetases (AARS) in human, animal or plant disease is a challenging work in progress. It does not matter in which biological model AARS are being studied, for all insights are relevant to understanding the complex pathophysiological mechanisms involved in disease production. By definition, a disease is “a pathological state characterized by an identifiable group of signs or symptoms.” But recognition of a pathological state implies a clear knowledge of the normal function of a particular cell, tissue, organ, or biochemical pathway. In the case of a chapter entitled “AARS and Disease,” this might seem to imply a complete understanding of normal primary and secondary AARS function. Wishful thinking. We are only beginning to understand the myriad of expanded functions mediated by class I and class II AARS. Thus a major barrier to our understanding the relationship between AARS and disease may be lifted through continued research into the diversity of species and enzyme-specific secondary functions of AARS.

Since the last time the general subject of AARS and disease associations was reviewed,¹ many of our observations remain qualitative. However, there has been a proliferation of knowledge on AARS due to progress in genome projects and the cloning and expression of functional new AARS genes. As we discover new biochemical pathways in which AARS participate, our ability to define AARS-associated pathologies will improve significantly. In that context, this chapter reviews our present knowledge of AARS and disease in two parts—(1) disease with an unquestioned relationship to AARS, and (2) diseases, or pathological mechanisms, in which AARS are presumed to be involved because of circumstantial evidence involving biochemical pathways influenced by AARS. First, autoimmune disease is defined and illustrated using the specific example of an idiopathic inflammatory myopathy, known as an “anti-synthetase syndrome.” Secondly, research is reviewed that encompasses a wide range of pathophysiological pathways (e.g., signal transduction in vascular smooth muscle and endothelial cells, apoptosis and immune responsiveness) that can involve AARS via their alternative or “non-canonical” functions.

This chapter is meant to provide an overview of the diverse observations that link AARS to human disease. An excellent resource for researching specific human AARS and disease associations, is the Human GeneCard Database (http://bioinfo.weizmann.ac.il/cards) maintained by the Weizmann Institute of Science.² Presently, thirty-seven Gene Cards representing human AARS are on file. This link summarizes primary and secondary function(s), chromosomal location and structural similarities, with links to pertinent literature citations. Information in this database is automatically extracted from various resources in the context of functional genomics and proteomics. Nomenclature on file has been approved by international consensus for about one third of genes encoded in the human genome. Approximately 20,000 more human genes will be added to this database as the human genome project nears completion.

Aminoacyl-tRNA Synthetase Related Disease

Autoimmune Disease

Autoimmune diseases³ are a group of clinically diverse conditions, all characterized by the production of abnormal antibody and/or cellular immune responses that adversely effect host tissues (Table 1). Autoantibodies are immunoglobulins that bind to host (self ) antigens. Low levels of some autoantibodies (e.g., rheumatoid factor) develop as an apparently normal phenomenon in the course of human aging. Presumably, long term exposure to “hidden” self antigens via cell turnover and/or death during the aging process can lead to generation of autoantibodies with minimal clinical impact. Infectious diseases, notably those caused by human parasitic nematodes (e.g., filaria), can generate antibody that is cross reactive with many human cytoplasmic antigens.⁴

Table 1

Human autoimmune diseases and corresponding autoantibodies.

One uncommon type of human autoimmune disease is known as an idiopathic inflammatory myopathy^5-10 (IIM). In this disease, patients demonstrate a spectrum of pulmonary, arthritic and/ or inflammatory muscle signs. A subset of IIM is now referred to as the “anti-synthetase syndrome.” The six known members of this disease subset are distinguishable by a highly enzyme-specific neutralizing autoantibody that inhibits aminoacylation by one particular cytoplasmic AARS.

Anti-Synthetase Syndrome

The history leading to the discovery of unique neutralizing anti-synthetase antibodies has been archived in the rheumatology literature.^11-22 To date, six different human cytoplasmic AARS have been identified as autoantigens in human anti-synthetase syndromes (Table 2). In each case, a patient's serum contains a specific autoantibody that reacts with and inhibits aminoacylation by one cytoplasmic AARS. Anti-tRNA synthetase antibodies are found in about one third of patients with the chronic inflammatory muscle or skin-and-muscle disorders known as polymyositis and dermatomyositis.

Table 2

Six known human neutralizing anti-tRNA synthetase antibodies.

Our understanding of exactly how AARS become autoantigens is incomplete. The lack of a consensus opinion based on current evidence may reflect different mechanisms responsible for each autoantibody. One clue to that possibility is that the specificity and immunological properties (e.g., epitopes recognized) of each anti-synthetase antibody differ greatly. Nonspecific antibodies can recognize short linear epitopes, or immunoprecipitate protein:RNA complexes. But true neutralizing anti-synthetase autoantibodies inhibit aminoacylation and can either precipitate AARS:tRNA complexes, or recognize isoacceptor tRNA alone. Classically, immunoprecipitation of HeLa cell extracts and amino acid specific aminoacylation inhibition have been used to identify “true” (neutralizing) anti-synthetase autoantibody. Interestingly, rarely is more than one anti-synthetase antibody ever found in a single patient. In a clinical study of 1,472 patients with suspected rheumatological disease, thirteen patients were found to have anti-AARS antibody by immunoprecipiation of HeLa cell extracts—4 persons had with Jo-1, three with PL-12, EJ in four and OJ in one person.¹¹ Immunology reference laboratories have screened tens of thousands of persons with myositis, connective tissue disease, interstitial lung disease and other rheumatological afflictions, searching for anti-synthetase autoantibody. Yet only six amino acid specific enzymes have been documented worldwide.

One of the six AARS involved in an anti-synthetase syndromes, IleRS, is a class I enzyme. Also, IleRS is the only one of these six enzymes that is a member of the high molecular weight eukaryotic multi-enzyme complex that contains IleRS, MetRS, AspRS, ArgRS, LysRS, GlnRS, LeuRS, the bifunctional GluRS-ProRS and the proteins p18, p38 and p43.²² Even though anti-synthetase syndromes are generally considered to be a subset of IIM, the disease can occur in the absence of clinically significant myositis. In such cases, interstitial lung disease is often present and usually requires immunosuppressive therapy. Therefore, anti-synthetase syndromes should be considered in patients with interstitial lung disease and anti-cytoplasmic antigen autoantibodies, or anti-nuclear antibodies in the context of an ill-defined autoimmune illness.

Pathology with Suspected AARS Association

Signal Transduction and Dinucleotide Oligophosphates (ApnA)

One of the first established alternative functions for a class II AARS, the E. coli LysRS, was the biosynthesis of the dinucleotide polyphosphates, Ap3A and Ap4A.³¹ The general formula for these dinucleotide polyphosphates is abbreviated “ApnA,” where “n” represents the number of phosphates bridging the two adeonsine moieties (Fig. 1). Over the past forty years, it has become clear that AARS are a primary source of ApnA in mammalian cells, but not all AARS can synthesize ApnA. Also, AARS can synthesize ApnA with or without the “main” substrate, tRNA.^32,33 In other species, additional classes of enzymes can form nucleotidylates (Ap4A phosphorylases in yeast, guanylyltransferases in yeast and brine shrimp, firefly luciferase) have the capacity to synthetase nucleotide oligophosphates (NpnN.)³⁴ The structural basis for ApnA synthesis in humans is presumably the same as that proposed for Ap4A synthesis by Thermus thermophilus SerRS.³⁵ In that model, the enzyme bound serine adenylate intermediate reacts with a second molecule of ATP to form ApnA. However, in the original studies of enzymatic synthesis of Ap3A and Ap4A by a purified bacterial lysyl-tRNA synthetase, synthesis was observed even without the addition of exogenous l-lysine. In the future, details of biochemical pathways involving dinucleotide oligophosphate production/hydrolysis will be better understood. At that point, we will be better equipped to design experiments examining the pathophysiological sequelae of up- or down-regulation of ApnA biosynthesis. Recently, it has been reported that vascular invasiveness of some bacterial pathogens is associated with Nudix hydrolases, enzymes that catalyze the hydrolysis of diadenosine tetra-, penta-, and hexaphosphates, to form ATP and ADP.³⁶

Figure 1

General structure of a diadenosine oligo-phosphate (ApnA). “n” represents the number of linked phosphate moieties.

ApnA are potent intercellular and intracellular signaling molecules that affect a wide variety of cellular processes via stimulation of a subset of cell surface purinoreceptors^37-51 (Table 3). What is difficult to discern is exactly how these compounds are regulated and how they interact with known signal transduction pathways. In cultured human promyelocytic leukemic cells (HL60), it has been proposed that Ap3A may bind to protein kinase C, similar to the phorbol esters that induce cellular differentiation. Cell surface purinergic receptors are classified as either P1 or P2, based on ligand specificity.^52-54 P1 (adenosine) receptors belong to the large family of G protein coupled receptors. P2 receptors are molecularly distinct from the P1 family, and they preferentially bind ATP and modulate phospholipase C and intracellular calcium. ApnA receptors are believed to belong to the P2 subset. Numerous P1 and P2 receptors subsets still are being defined by cDNA sequencing. Some degree of heterogeneity in ApnA receptors between species and cell types may reflect different affinities to dinucleotides. In humans, ApnA receptors have been shown on a wide variety of cell types including brain, liver, kidney, cardiac, spleen, bladder, adipose, bone and endothelial cells.^55-57

Table 3

Reported biological activities of diadenosine oligophosphates in mammalian cells.

Perspectives

Our ability to recognize physiologically important synthetase-disease associations will improve as research progresses in understanding eukaryotic AARS structure-function relationships. As the subtle details of catalytic site – substrate chemistries unfold, pharmacological interventions will be designed to test prototype inhibitors of AARS-controlled pathways. Most certainly, our definition of “AARS-Associated Disease” will expand. Not only will AARS inhibitors be considered as novel anti-infective drugs (see the chapter, Synthetases and Drug Targets), but their potential therapeutic value can be assessed in far reaching cellular processes—as mediators of vasomotor control, endothelial cell and neutrotransmitter function, apoptosis, immune modulation and regulation of cell growth and differentiation of any tissue.^97-98 New diagnostic techniques may be developed to identify abnormal or injured cells expressing abnormal AARS, or if dysregulation of dinucleotide oligophosphate receptors occurs on abnormal cells. For example, research on the immunopathology of Alzheimer's disease concluded that TrypRS, localized in the abnormal neurons of tryptamine treated mouse brain, can be used as a disease marker.⁹⁹

Novel therapeutic approaches to an array of human diseases may arise from understanding pathophysiological pathways involving AARS. For example, human mitochondrial tRNA gene mutations have been associated with a variety of neurogenerative and chronic diseases.¹⁰⁰ Under conditions where these point mutations cause disease via decreased activity of the corresponding AARS, therapeutic upregulation of a specific AARS may overcome the deleterious effects of the tRNA mutation.¹⁰¹ In the case of human TyrRS, a natural fragment of the entire gene produced by alternate splicing has been shown to be angiostatic.¹⁰² In human retinal diseases such as macular degeneration where there is abnormal vascular proliferation, this angiostatic effect may prove therapeutic.¹⁰³ The discovery that human LysRS and possibly other class II AARS are non-randomly incorporated into HIV-1 virions, should fuel new hypotheses on how to disrupt viral replication.¹⁰⁴ Since MetRS, IleRS and LeuRS in humans exhibit continuous editing of incorrectly charged tRNAs, it has been suggested that inhibition of factors disrupting translational accuracy (i.e., homocysteine incorporation into protein) may be useful to manage cardiovascular disease.¹⁰⁵

As the intricacies of the human genome are deciphered, new insights will be gleaned from the observation of genetic clustering and organization of certain AARS within candidate disease loci.²⁹ Information on the genomic organization of human AARS, and measurement of tissue specific AARS gene expression may yield important insight into physiologically relevant AARS functions. Comparative structure function studies using host and pathogen AARS can identify phylogenetic anomalies that could be targeted for disruption by new therapies.

As expressed AARS “gene fragments”, products of alternate splicing, isoforms or pseudogenes are encountered in the study of normal and disease states, their functional significance as cytokines, ApnA producers, etc. deserves careful study. For example, in the plant, Arabadopsis thaliana, transcribed cysteinyland asparaginyl-tRNA synthetase genes are duplicated and quadruplicated, respectively.¹⁰⁶ The absence of intact conserved substrate binding sites in expressed isoforms of AsnRS in Arabadopsis, suggests that these products are incapable of aminoacylation. Other biological activities have not yet been identified. Similarly, in the human filarial nematode parasite, Brugia malayi, cytoplasmic AsnRS is a multicopy gene¹⁰⁷ that becomes an immunodominant antigen in the sera of infected persons.¹⁰⁸ While the cytokine-like properties of human TyrRS and AARS-associated p43 have been recently identified, the full spectrum of immunological activities of other human or other eukaryotic AARS has not been fully explored. In the future, research to define the biological activities of what now are considered spontaneous deletion derivatives may broaden our understanding of AARS structure-function relationships.

Dedication

We dedicate this chapter to the memory of Carmen Berthet-Colominas, an extraordinary human being who devoted her life to solving the mysteries of protein structure and function. We trust that the disease that robbed this world of her many talents, someday will be conquered in no small part by the scientific insights she has provided.

Figure 2

Carmen Berthet-Colominas.

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