Xpr1 is an Atypical G-protein Coupled Receptor that Mediates Xenotropic and Polytropic Murine Retrovirus Neurotoxicity
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 crosslinking studies show that Xpr1 is associated with the G? subunit of the G-protein heterotrimer. Activation of adenylate cyclase rescued the cells from XMRV toxicity, indicating that toxicity resulted from reduced G-protein-mediated 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 apoptosis of infected cells. We show that this pathway also is responsible for the classic toxicity of the polytropic mink cell focus-forming (MCF) retrovirus in mink cells. Although it now seems clear that 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.