Review
Alpha-actinin: A multidisciplinary protein with important role in B-cell driven autoimmunity

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Abstract

Alpha-actinin (α-actinin) is a ubiquitous cytoskeletal protein, which belongs to the superfamily of filamentous actin (F-actin) crosslinking proteins. 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 and thus, it seems to bear multiple important roles in the cell by linking the cytoskeleton to many different transmembrane proteins in a variety of junctions. Four isoforms of human α-actinin have already been identified namely, the “muscles” α-actinin-2 and α-actinin-3 and the “non-muscles” α-actinin-1 and α-actinin-4. 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. They are generally believed to represent key structural components of large-scale F-actin cohesion in cells required for cell shape and motility. α-Actinin-2 has been implicated in myopathies such as nemalin body myopathy, hypertrophic and dilated cardiomyopathy and it may have at least an indirect pathogenetic role in diseases of the central nervous system (CNS) like schizophrenia, epilepsy, ischemic brain damage, CNS lupus and neurodegenerative disorders. The role of “non-muscle” α-actinins in the kidney seems to be crucial as an essential component of the glomerular filtration barrier. Therefore, they have been implicated in the pathogenesis of familial focal segmental glomerulosclerosis, nephrotic syndrome, IgA nephropathy, focal segmental glomerulosclerosis and minimal change disease. α-Actinin is also expressed on the membrane and cytosol of parenchymal and ductal cells of the liver and it seems that it interacts with hepatitis C virus in an essential way for the replication of the virus. Finally α-actinin, especially α-actinin-4, has been implicated in cancer cell progression and metastasis, as well as the migration of several cell types participating in the immune response. Based on these functions, the accumulating reported evidence of the importance of α-actinin as a target autoantigen in the pathogenesis of autoimmune diseases, particularly systemic lupus erythematosus and autoimmune hepatitis, is also discussed along with the possible perspectives that are potentially emerging from the study of this peculiar molecule in health and disease.

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

  • 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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