Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells.

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2008; 105(20):7235-9. DOI: 10.1073/pnas.0802301105
Source: PubMed

ABSTRACT Osteopontin (Opn) contributes to diverse biological processes that include immune responses, vascularization, and bone formation. Until recently, studies describing the activities of Opn have focused on the cytokine-like properties of the secreted protein. Here, we show that alternative translation of a single Opn mRNA species generates a secreted and intracellular isoform. Utilization of a 5' canonical translation start site generates a protein that includes an N-terminal signal sequence allowing targeting to secretory vesicles and cytokine secretion, whereas usage of a downstream start site generates a shortened protein that lacks the N-terminal signal sequence and localizes mainly to cytoplasm. The coordinated action of these Opn gene products regulates the functional phenotype of subsets of dendritic cells.

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    ABSTRACT: Follicular helper T cells (TFH cells) and follicular regulatory T cells (TFR cells) regulate the quantity and quality of humoral immunity. Although both cell types express the costimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that activation of ICOS in CD4(+) T cells promoted interaction of the p85α regulatory subunit of the signaling kinase PI(3)K and intracellular osteopontin (OPN-i), followed by translocation of OPN-i to the nucleus, its interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 by OPN-i was essential for sustained responses of TFH cells and TFR cells and regulation of the germinal center B cell response to antigen. Thus, the p85α-OPN-i axis represents a molecular bridge that couples activation of ICOS to Bcl-6-dependent functional differentiation of TFH cells and TFR cells; this suggests new therapeutic avenues to manipulate the responses of these cells.
    Nature Immunology 12/2014; 16(1). DOI:10.1038/ni.3050 · 24.97 Impact Factor
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    Journal of Neuroinflammation 12/2014; 11(1):197. DOI:10.1186/s12974-014-0197-0 · 4.90 Impact Factor
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    ABSTRACT: Osteopontin (OPN) has been implicated widely in tumor growth and metastasis but the range of its contributions are not yet fully understood. In this study, we show that genetic ablation of OPN in the mouse sensitizes them to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Opn deficient mice (Opn-/- mice) exhibited enhanced production of proinflammatory cytokines and compensatory proliferation. Administering OPN antibody or recombinant OPN protein to wild type (WT) or Opn-/- mice-derived macrophages, respectively, had little effect on cytokine production. In contrast, overexpression of intracellular Opn (iOpn) in Opn-deficient macrophages strongly suppressed production of proinflammatory cytokines. In addition, we found iOPN was able to interact with the pivotal Toll-like receptor (TLR) signaling protein MyD88 in macrophages after stimulation with cellular debris, thereby disrupting TLR signaling in macrophages. Our results indicated that iOPN was capable of functioning as an endogenous negative regulator of TLR-mediated immune responses, acting to ameliorate production of proinflammatory cytokines and curtail DEN-induced hepatocarcinogenesis. Together, our results expand the important role of OPN in inflammation-associated cancers and deepen its relevance for novel treatment strategies in liver cancer.
    Cancer Research 11/2014; 75(1). DOI:10.1158/0008-5472.CAN-14-0615 · 9.28 Impact Factor

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