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Title: Role of Jumonji c-domain containing protein 6 (JMJD6) in infectivity of foot-and-mouth disease virus

Author
item Lawrence, Paul
item RAI, DEVENDRA - Oak Ridge Institute For Science And Education (ORISE)
item CONDERINO, JOSEPH - Oak Ridge Institute For Science And Education (ORISE)
item UDDOWLA, SABENA - University Of Central Florida
item Rieder, Aida - Elizabeth

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/11/2016
Publication Date: 2/5/2016
Citation: Lawrence, P.J., Rai, D.K., Conderino, J.S., Uddowla, S., Rieder, A.E. 2016. Role of Jumonji c-domain containing protein 6 (JMJD6) in infectivity of foot-and-mouth disease virus. Virology. 492:38-52. doi: 10.1016/j-virol.2016.02.005.

Interpretive Summary: Foot and mouth disease (FMD) is a devastating disease of livestock caused by a virus FMDV. Understanding how the virus infects the animal cells is critical to develop better methods to prevent infection. In this study, we have identified for the first time a cellular molecule, called JMJD6, that serves as receptor and allows entry FMDV into cells to initiate infection. This new information contributes to the knowledge of virus-host interaction and has potential for the development of antiviral disease intervention strategies.

Technical Abstract: Foot-and-mouth disease virus (FMDV) can utilize as many as three distinct groups of receptor molecules to attach and enter a susceptible host cell. Four integrin heterodimers (alphavBeta1, alphavBeta3, alphavBeta6, and alphavBeta8) can function as the primary receptor for FMDV field strains. FMDV multiply passaged in cell culture frequently adapts to use a secondary receptor: heparan sulfate (HS). In rare instances, FMDV attachment is facilitated by a third as yet unidentified receptor. A unique set of capsid mutations derived from a soluble integrin resistant FMDV mutant were incorporated into a FMDV infectious clone that exhibited an affinity for Jumonji C-domain containing protein 6 (JMJD6). Infection with the infectious clones triggered re-localization of JMJD6 from the cell surface and cytoplasm to the nucleus. Furthermore, attachment was impeded by both pre-treatment of cells with anti-JMJD6 and separately by co-incubation with soluble JMJD6 but not HS or soluble alphavBeta6. JMJD6 antibodies targeted to either the N or C-terminus negatively impacted infectivity suggesting a membrane orientation with both domains on the extracellular surface. Recombinant JMJD6 and the infectious clone co-purified by reciprocal co-immunoprecipitation. Molecular docking models revealed the JMJD6 C-terminus to be a prominent site of interaction with the mutated VP1 capsid protein. We conclude JMJD6 plays a role in FMDV infectivity when VP1 capsid mutations are displayed that preclude usage of traditional receptors.