title: Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein-Barr virus BARF1.
abstract: The ubiquitous EBV causes infectious mononucleosis and is associated with several types of cancers. The EBV genome encodes an early gene product, BARF1, which contributes to pathogenesis, potentially through growth-altering and immune-modulating activities, but the mechanisms for such activities are poorly understood. We have determined the crystal structure of BARF1 in complex with human macrophage-colony stimulating factor (M-CSF), a hematopoietic cytokine with pleiotropic functions in development and immune response. BARF1 and M-CSF form a high-affinity, stable, ring-like complex in both solution and the crystal, with a BARF1 hexameric ring surrounded by three M-CSF dimers in triangular array. The binding of BARF1 to M-CSF dramatically reduces but does not completely abolish M-CSF binding and signaling through its cognate receptor FMS. A three-pronged down-regulation mechanism is proposed to explain the biological effect of BARF1 on M-CSF:FMS signaling. These prongs entail control of the circulating and effective local M-CSF concentration, perturbation of the receptor-binding surface of M-CSF, and imposition of an unfavorable global orientation of the M-CSF dimer. Each prong may reduce M-CSF:FMS signaling to a limited extent but in combination may alter M-CSF:FMS signaling dramatically. The downregulating mechanism of BARF1 underlines a viral modulation strategy, and provides a basis for understanding EBV pathogenesis.
authors: Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors: Ann Hye-Ryong
authors: AH
authors: Shim
authors: Rhoda Ahn
authors: RA
authors: Chang
authors: Xiaoyan
authors: X
authors: Chen
authors: Richard
authors: R
authors: Longnecker
authors: Xiaolin
authors: X
authors: He
mesh_terms: D002151:Calorimetry; D018360:Crystallography, X-Ray; D019281:Dimerization; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry*; D010766:Phosphorylation; D011487:Protein Conformation; D015398:Signal Transduction / Q000235:genetics*; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C086495:BARF1 protein, Human herpesvirus 4; D046912:Multiprotein Complexes; D014764:Viral Proteins; D016173:Macrophage Colony-Stimulating Factor