NAMPT Antagonizes Tegument Protein Incorporation to Restrict Herpesvirus Lytic Replication

Abstract

Metabolic enzymes fuel the synthesis of macromolecules that underpin the proliferation of cells and propagation of pathogens. NAD is a key cofactor for enzymes catalyzing metabolic reactions. We report that NAMPT, the rate-limiting enzyme of the salvage pathway of NAD synthesis, antagonizes tegument protein incorporation and restricts herpesvirus lytic replication in an enzyme-independent manner. We demonstrated that NAMPT was packaged into the virion and reduced lytic replication of human herpes simplex virus 1 (HSV-1). Mechanistically, NAMPT targets two core tegument proteins, UL36 and UL37 that mesh a scaffold for viral tegumentation during lytic replication. As such, NAMPT competitively antagonizes the incorporation of diverse tegument proteins into the virion, impairing viral tegumentation and infectivity of the progeny. Microscopy analysis indicates that NAMPT localizes to the TGN, which HSV-1 capsids bud into during tegumentation. Finally, NAMPT exhibited antiviral activity against multiple herpesviruses and loss of NAMPT rendered mice highly susceptible to HSV-1 infection. This study defines a new restriction factor targeting herpesvirus tegumentation, revealing a metabolism-independent antiviral activity of a metabolic enzyme.