Xpr1 Is an Atypical G-Protein-Coupled Receptor That Mediates Xenotropic and Polytropic Murine Retrovirus Neurotoxicity

Abstract

Xenotropic murine leukemia virus-related virus (XMRV) was first identified in human prostate cancer tissue and was later found in a high percentage of humans with chronic fatigue syndrome (CFS). While exploring potential disease mechanisms, we found that XMRV infection induced apoptosis in SY5Y human neuroblastoma cells, suggesting a mechanism for the neuromuscular pathology seen in CFS. Several lines of evidence show that the cell entry receptor for XMRV, Xpr1, mediates this effect, and chemical cross-linking studies show that Xpr1 is associated with the G␤ subunit of the G-protein heterotrimer. The activation of adenylate cyclase rescued the cells from XMRV toxicity, indicating that toxicity resulted from reduced G-protein-mediated cyclic AMP (cAMP) signaling. Some proteins with similarity to Xpr1 are involved in phosphate uptake into cells, but we found no role of Xpr1 in phosphate uptake or its regulation. Our results indicate that Xpr1 is a novel, atypical G-protein-coupled receptor (GPCR) and that xenotropic or polytropic retrovirus binding can disrupt the cAMP-mediated signaling function of Xpr1, leading to the apoptosis of infected cells. We show that this pathway is also responsible for the classic toxicity of the polytropic mink cell focus-forming (MCF) retrovirus in mink cells. Although it now seems clear that the detection of XMRV in humans was the result of sample contamination with a recombinant mouse virus, our findings may have relevance to neurologic disease induced by MCF retroviruses in mice.

Vtc5, a Novel Subunit of the Vacuolar Transporter Chaperone Complex, Regulates Polyphosphate Synthesis and Phosphate Homeostasis in Yeast

“…It is a homolog of the mammalian phosphate exporter Xpr1. Because both proteins localize to the plasma membrane and interact with ␤ subunits of G-proteins (23)(24)(25), they may have similar functions in exporting P i .…”

Inorganic Phosphate Export by the Retrovirus Receptor XPR1 in Metazoans

“…Entry requires specific binding between receptors and the amino-terminal receptor-binding domain (RBD) of the viral envelope glycoproteins (Env) (Battini et al, 1995;Fass et al, 1997). In the absence of reliable exofacial antibodies (data not shown; Vaughan et al, 2012), we monitored cell-surface expression of XPR1 with a soluble ligand derived from X-MLV Env RBD (XRBD) ( Figure 1A). XRBD binding to human HEK293T cells was specifically abolished upon introduction of a small interfering RNA (siRNA) targeting human XPR1 (siXPR1) (p value % 0.001) ( Figure 1B).…”

“…Proteins harboring an SPX domain play key roles in phosphate regulation in yeast and plants (Secco et al, 2012a(Secco et al, , 2012b. Moreover, the SPX domain of XPR1 has been shown to interact with the b subunit of the G protein heterotrimers (Gß) and modulate cyclic AMP levels (Vaughan et al, 2012). To address the potential role of SPX in phosphate efflux, we performed complementation assays with a human XPR1 construct recognized by XRBD, lacking the entire SPX domain (hDSPX) and properly expressed at the plasma membrane ( Figure 3D).…”

Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection

“…Although Fr98 does not infect neurons, virus infection in the CNS results in seizures (10,15), suggesting an indirect mechanism of neuronal damage. Furthermore, XPR1, the receptor for polytropic retroviruses, is expressed by neurons, and binding of this receptor by virus proteins induces neurotoxicity (50). Neurons do express Y1R, Y2R, and Y5R, and stimulation through these receptors has been shown to limit seizures in animal models of epilepsy, possibly by regulation of glutamate release (51).…”