ReviewAlpha-actinin: A multidisciplinary protein with important role in B-cell driven autoimmunity
Introduction
Discovered more than 40 years ago as a component of skeletal muscles, alpha-actinin (α-actinin), was one of the first described muscle molecules with in-vitro crosslinking function with filamentous actin (F-actin) [1]. Later on, α-actinin was also identified in non-muscle cells [2] while extensive studies have defined its molecular structure and the in-vitro activity of F-actin–α-actinin crosslinking.
α-Actinin is a ubiquitous cytoskeletal protein, which belongs to the superfamily of F-actin crosslinking proteins, together with spectrin, dystrophin, and their homologues and isoforms [3]. It is present in multiple subcellular regions of both muscle and non-muscle cells, including cell–cell and cell–matrix contact sites, cellular protrusions and stress fiber dense regions [4]. At present, four isoforms of human α-actinin have been identified (Table 1): “non-muscle” α-actinin-1 [5], “muscle” α-actinin-2 [6], “muscle” α-actinin-3 [6] and the more recently characterized “non-muscle” α-actinin-4 [7]. α-Actinins-2 and -3 form part of the contractile machinery by anchoring actin filaments at the Z lines in striated muscles and dense bodies in smooth muscle cells [4]. The expression of genes encoding “non-muscle” α-actinins-1 and -4 is widespread. The latter α-actinins by interacting not only with F-actin but also with a large number of cytoskeletal and membrane proteins are involved in the organization of cell cytoskeleton and adjacent to adherent junctions. As a result α-actinin is considered to play multidisciplinary as well as important roles inside the cell, linking the cytoskeleton to many different transmembrane proteins, regulating the activity of a variety of receptors and connecting the cytoskeleton with an ever growing list of signaling pathways and adhesion molecules [3], [4], [8], [9], [10], [11].
Not surprisingly, this multifunctional and also fundamental cell molecule has recently gained attention as a possible dominant target autoantigen in autoimmune diseases, especially systemic lupus erythematosus (SLE) and autoimmune hepatitis type-1 (AIH-1). Indeed, accumulating volume of evidence indicate that anti-dsDNA autoantibodies (Abs) may contribute to the pathogenesis of SLE-related glomerulonephritis by cross-reacting with α-actinin in murine models as well as in humans [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. On the other hand, anti-α-actinin Abs have been detected in the sera of more than 40% of patients with AIH-1, characterizing, in combination with anti-F-actin (AFA) Abs, a subset of patients with clinically and histologically severe form of the disease [24], [25].
The aim of the present review is to summarize the role of α-actinin in health and disease by focusing on the immune responses and the existing evidence on the importance of α-actinin as a target autoantigen in autoimmune diseases.
Section snippets
α-Actinin structure (Table 1)
α-Actinin is a 100 kDa peptide harboring an amino-terminal-calponin-homology (CH) domain (composed of two CH parts), a central rod containing spectrin repeats and a calmodulin-like calcium-binding domain (CaM) at the carboxy-terminus [3], [26], [27] (Fig. 1). Εach domain of α-actinin has been solved separately by X-ray crystallography [26], [28], [29], but the structure of the complete α-actinin monomer or dimer has not yet been determined at high resolution analysis. The functional unit of
The role of α-actinin in health and disease
There are four known α-actinin genes, which are highly homologous and highly conserved among species [32], [33]. However, despite extensive research, the precise functions of α-actinin isoforms as well as the precise role and significance of their binding to F-actin particularly in-vivo, have been elusive (Table 1). They are generally believed to represent key structural components of large-scale F-actin cohesion in cells required for cell shape and motility [4]. In addition, their subcellular
Take-home messages
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α-Actinin has a complicated function being much more than a simple F-actin-crosslinking protein. One of the current challenges is to explore the diverse functions of α-actinin in different tissues, where it is expressed using modern genetic techniques and understand its multidisciplinary role in a wide range of human diseases. More specifically, α-actinin seems to play an important role in the immune response in respect to cell migration to sites of inflammation, while an exciting new
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