Intracellular osteopontin (iOPN) and immunity
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Intracellular osteopontin (iOPN) and immunity Makoto Inoue • Mari L. Shinohara
Published online: 7 December 2010 Ó Springer Science+Business Media, LLC 2010
Abstract Osteopontin (OPN) is a protein involved in various pathophysiological events. OPN has been studied as a secreted protein, but recent reports showed that OPN can be found in the cytoplasm and the nucleus. Therefore, some OPN molecules are not secreted and stay in cells. Such intracellular OPN (iOPN) has biological functions distinct from secreted OPN (sOPN). iOPN is involved in cytoskeletal rearrangement and in signal transduction pathways downstream of innate immune receptors, such as Toll-like receptors (TLRs), as an adaptor or scaffolding protein. Although sOPN and iOPN are generated from the same Opn mRNA species, biological outcomes mediated by two isoforms can be different. It would be necessary to delineate which isoform of OPN is responsible for pathophysiological events. Keywords Osteopontin (OPN) Intracellular OPN (iOPN) Secreted OPN (sOPN) Innate immunity EAE MS Autoimmune diseases T helper cell polarization Dendritic cells (DCs)
What is osteopontin (OPN)? Osteopontin (OPN), also known as early T lymphocyte activation 1 (Eta-1), is a glycoprotein expressed by a variety of tissues and cell types. OPN is multifunctional, and its functions are linked to various physiological and pathological events. OPN was first described by Hynes and colleagues [1] as a phosphoprotein secreted by transformed cells lines. Heinegard’s group [2] cloned the bone-specific sialoprotein, which plays a role as a matrix protein, from the rat osteosarcoma phage kgt11 library and termed the protein ‘‘osteopontin’’. The mouse Opn gene was first cloned by Denhardt’s group as a tumor promoter (TPA) inducible gene [3]. Cantor and colleagues [4] independently identified OPN as Eta-1, which is abundantly expressed in activated T cells. This finding was the first M. Inoue M. L. Shinohara (&) Department of Immunology, School of Medicine, Duke University, 338 Jones Building, DUMC 3010, Durham, NC 27710, USA e-mail: [email protected]
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report to directly connect OPN to immunity. OPN was identified and has been studied as an extracellular protein. Therefore, unless specifically noted, any previous studies were performed as OPN to be a secreted protein. We will discuss a novel intracellular isotype of OPN (iOPN) later in this review. OPN can act as modulators of cell adhesion as well as autocrine and paracrine factors by interacting with cell surface receptors, such as integrins. OPN contains an integrin-binding RGD motif that is recognized by integrins avb3, avb1, avb5, avb6, a5b1, and a8b1 [5–10]. In contrast, integrins a9b1 and a4b1 bind to the cryptic epitope (SLAYGLR motif in mice) of OPN that is exposed upon cleavage by thrombin [11–13]. OPN is also detected by CD44, specifically by isotypes containing v6-v7 regions, and by integrin axb2 [14, 15]. Function of OPN is regulated by post-translational modifications,
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