Optineurin Is a Universal Entry Receptor for Herpesviruses

Optineurin is a protein expressed in many human tissues. Mutations of optineurin were shown to be associated with major human diseases, such as primary open-angle glaucoma (a blinding disease) and amyotropic lateral sclerosis (a lethal condition). The functions of this protein, which was discovered relatively recently, are mostly unknown, or are not fully characterized. In this study, we investigated whether optineurin plays a role in regulating infections of multiple human herpesviruses (herpes simplex viruses-1 and -2, and human cytomegalovirus), and found that it functions to support the herpesvirus infection. After experimentally ruling out alternative hypotheses regarding its mechanism of action, we found that optineurin interacts with the viral envelope glycoprotein B (gB) and that such an interaction is required for membrane fusion and virus internalization into the cells. Using rigorous criteria of a viral entry receptor, we established that optineurin fulfills all these criteria and is qualified as the viral entry receptor for the three herpesviruses tested, and perhaps other herpesviruses that express the highly conserved ligand, gB. We also demonstrated that optineurin represents an essential component of the herpesvirus entry machinery that is required for infection in vitro and in vivo. For the first time, this study establishes the cell-surface receptor properties of optineurin, utilizing the virus as a biological probe. Discovery of the receptor optineurin will indubitably both advance the understanding of herpesvirus entry machinery and enlighten cell biology with a new receptor molecule that may perform similar receptor functions in non-infection conditions, or optineurin-regulated devastating human diseases.