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RANKL-RANK signaling regulates expression of xenotropic and polytropic virus receptor (XPR1) in osteoclasts.

ABSTRACT: Formation of multinucleated bone-resorbing osteoclasts results from activation of the receptor activated NF-kappaB ligand (RANKL)-receptor activated NF-kappaB (RANK) signaling pathway in primary bone marrow macrophages and a macrophage cell line (RAW 264.7). Osteoclasts, through bone remodeling, are key participants in the homeostatic regulation of calcium and phosphate levels within the body. Microarray analysis using Gene Expression Dynamic Inspector (GEDI) clustering software indicated that osteoclast differentiation is correlated with an increase in xenotropic and polytropic virus receptor 1 (XPR1) mRNA transcripts. XPR1 is a receptor of the xenotropic and polytropic murine leukemia virus and homolog of yeast Syg1 and plant Pi transporter PHO1. Quantitative PCR was used to validate the up-regulation of XPR1 message following RANKL stimulation in both primary bone marrow cells and a macrophage cell line. Immunostaining for the XPR1 protein showed that there is translocation of XPR1 to the membranes of the sealing zone in mature osteoclasts. This study is the first to demonstrate that the expression of retro-viral receptor, XPR1, is regulated by RANKL-RANK signaling.

SUBMITTER: Sharma P

PROVIDER: S-EPMC4667747 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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RANKL-RANK signaling regulates expression of xenotropic and polytropic virus receptor (XPR1) in osteoclasts.

Sharma Parul P Patntirapong Somying S Hann Steven S Hauschka Peter V PV

Biochemical and biophysical research communications 20100713 2

Formation of multinucleated bone-resorbing osteoclasts results from activation of the receptor activated NF-kappaB ligand (RANKL)-receptor activated NF-kappaB (RANK) signaling pathway in primary bone marrow macrophages and a macrophage cell line (RAW 264.7). Osteoclasts, through bone remodeling, are key participants in the homeostatic regulation of calcium and phosphate levels within the body. Microarray analysis using Gene Expression Dynamic Inspector (GEDI) clustering software indicated that o ...[more]

PMID: 20633538

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Project description:BackgroundThe evolutionary interactions between retroviruses and their receptors result in adaptive selection of restriction variants that can allow natural populations to evade retrovirus infection. The mouse xenotropic/polytropic (X/PMV) gammaretroviruses rely on the XPR1 cell surface receptor for entry into host cells, and polymorphic variants of this receptor have been identified in different rodent species.ResultsWe screened a panel of X/PMVs for infectivity on rodent cells carrying 6 different XPR1 receptor variants. The X/PMVs included 5 well-characterized laboratory and wild mouse virus isolates as well as a novel cytopathic XMV-related virus, termed Cz524, isolated from an Eastern European wild mouse-derived strain, and XMRV, a xenotropic-like virus isolated from human prostate cancer. The 7 viruses define 6 distinct tropisms. Cz524 and another wild mouse isolate, CasE#1, have unique species tropisms. Among the PMVs, one Friend isolate is restricted by rat cells. Among the XMVs, two isolates, XMRV and AKR6, differ from other XMVs in their PMV-like restriction in hamster cells. We generated a set of Xpr1 mutants and chimeras, and identified critical amino acids in two extracellular loops (ECLs) that mediate entry of these different viruses, including 3 residues in ECL3 that are involved in PMV entry (E500, T507, and V508) and can also influence infectivity by AKR6 and Cz524.ConclusionWe used a set of natural variants and mutants of Xpr1 to define 6 distinct host range variants among naturally occurring X/PMVs (2 XMV variants, 2 PMVs, 2 different wild mouse variants). We identified critical amino acids in XPR1 that mediate entry of these viruses. These gammaretroviruses and their XPR1 receptor are thus highly functionally polymorphic, a consequence of the evolutionary pressures that favor both host resistance and virus escape mutants. This variation accounts for multiple naturally occurring virus resistance phenotypes and perhaps contributes to the widespread distribution of these viruses in rodent and non-rodent species.

Project description:The differential susceptibilities of mouse strains to xenotropic and polytropic murine leukemia viruses (X-MLVs and P-MLVs, respectively) are poorly understood but may involve multiple mechanisms. Recent evidence has demonstrated that these viruses use a common cell surface receptor (the X-receptor) for infection of human cells. We describe the properties of X-receptor cDNAs with distinct sequences cloned from five laboratory and wild strains of mice and from hamsters and minks. Expression of these cDNAs in resistant cells conferred susceptibilities to the same viruses that naturally infect the animals from which the cDNAs were derived. Thus, a laboratory mouse (NIH Swiss) X-receptor conferred susceptibility to P-MLVs but not to X-MLVs, whereas those from humans, minks, and several wild mice (Mus dunni, SC-1 cells, and Mus spretus) mediated infections by both X-MLVs and P-MLVs. In contrast, X-receptors from the resistant mouse strain Mus castaneus and from hamsters were inactive as viral receptors. These results suggest that X-receptor polymorphisms are a primary cause of resistances of mice to members of the X-MLV/P-MLV family of retroviruses and are responsible for the xenotropism of X-MLVs in laboratory mice. By site-directed mutagenesis, we substituted sequences between the X-receptors of M. dunni and NIH Swiss mice. The NIH Swiss protein contains two key differences (K500E in presumptive extracellular loop 3 [ECL 3] and a T582 deletion in ECL 4) that are both required to block X-MLV infections. Accordingly, a single inverse mutation in the NIH Swiss protein conferred X-MLV susceptibility. Furthermore, expression of an X-MLV envelope glycoprotein in Chinese hamster ovary cells interfered efficiently with X-MLV and P-MLV infections mediated by X-receptors that contained K500 and/or T582 but had no effect on P-MLV infections mediated by X-receptors that lacked these amino acids. In contrast, moderate expression of a P-MLV (MCF247) envelope glycoprotein did not cause substantial interference, suggesting that X-MLV and P-MLV glycoproteins interfere nonreciprocally with X-receptor-mediated infections. We conclude that P-MLVs have become adapted to utilize X-receptors that lack K500 and T582. A penalty for this adaptation is a reduced ability to interfere with superinfection. Because failure of interference is a hallmark of several exceptionally pathogenic retroviruses, we propose that it contributes to P-MLV-induced diseases.

Dataset Information

RANKL-RANK signaling regulates expression of xenotropic and polytropic virus receptor (XPR1) in osteoclasts.

Publications

RANKL-RANK signaling regulates expression of xenotropic and polytropic virus receptor (XPR1) in osteoclasts.

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