A Virally Encoded DeSUMOylase Activity Is Required for Cytomegalovirus Reactivation from Latency

Abstract

Summary: A subset of viral genes is required for the long-term latent infection of hematopoietic cells by human cytomegalovirus (HCMV). Here, we show that a latency-associated gene product (LUNA) promotes the disruption of cellular PML bodies during latency. Mutation and inhibitor studies reveal that LUNA encodes a deSUMOylase activity responsible for this disruption. Specifically, LUNA encodes a conserved Asp-Cys-Gly motif common to all deSUMOylases. Importantly, mutation of the putative catalytic cysteine is sufficient to reverse LUNA-mediated PML dispersal and markedly reduces the efficiency of viral reactivation. The depletion of PML from cells is sufficient to rescue the reactivation of the LUNA-deficient viruses, arguing that targeting PML is an important biological role of LUNA. Finally, we demonstrate that reactivation of naturally latent HCMV is blocked by deSUMOylase inhibitors. Thus, latent HCMV primes the cellular environment for efficient reactivation via the activity of a virally encoded deSUMOylase. : Poole et al. provide evidence that human cytomegalovirus removes anti-viral ND10 structures during latency. This serves to prime a cellular environment that can support reactivation as latently infected cells differentiate. This is achieved via the activity of a viral deSUMOylase that targets SUMOylated PML, an essential component required for ND10 formation. Keywords: cytomegalovirus, latency, deSUMOylase, PML, reactivation