DISINTEGRIN-LIKE DOMAIN IN KSHV ENCODED gB IS A NECESSITY TO PROMOTE VIRUS LATENCY

Abstract

KSHV glycoprotein B (gB) is a lytic structural protein expressed on the envelope of mature virions and on the membrane of cells supporting lytic infection. Previous studies have identified that in addition to the role of envelope-associated gB in virus binding, entry, and egress, cell membrane-bound gB has a role in promoting cellular attachment and virus latency, suggesting its involvement in KSHV pathogenesis. In addition to the more common integrin recognition motif, RGD (Arg-Gly-Asp), KSHV gB uniquely possesses a disintegrin-like domain (DLD). DLD is known to exert anti-integrin effects. In order to understand the role of DLD in gB, we generated recombinant gB lacking a functional DLD and tested it in biochemical and functional assays. Here we provide evidence demonstrating the role of DLD in regulating the function of gB-induced signaling critical to suppressing virus reactivation. Through screening phage display peptide library, [alpha]9[beta]1, a non-RGD binding integrin, was identified as a potential receptor for the DLD in KSHV gB. However, gB with an intact DLD can still exert its inhibitory effects on virus reactivation in 293 cells that do not express [alpha]9 integrins; possibly via other [beta]1 integrins. Such findings are an asset to further understand the biology of gB--especially in terms of appreciating roles of different domains within the same protein critical for its net function in the virulence.