Poole, E; Lau, J; Kew, V; Murray, M; Stamminger, T; Sinclair, J; Reeves, M; (2018) A virally encoded de-sumoylase activity is required for cytomegalovirus reactivation from latency. Cell Reports , 24 (3) pp. 594-606. 10.1016/j.celrep.2018.06.048.

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Abstract

A subset of viral genes is required for the long term latent infection of haematopoietic 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 novel de-sumoylase activity responsible for this disruption. Specifically, LUNA activity expressed a conserved Asp-Cys-Gly motif common to all de-sumoylases. Importantly, mutation of the putative catalytic cysteine was sufficient to reverse LUNA mediated PML dispersal and markedly reduced the efficiency of viral reactivation. The depletion of PML from cells was sufficient to rescue the reactivation of the LUNA-deficient viruses arguing that targeting PML was an important biological role of LUNA. Finally, we demonstrate that reactivation of naturally latent HCMV is blocked by de-sumoylase inhibitors. Thus latent HCMV primes the cellular environment for efficient reactivation via the activity of a virally encoded de-sumoylase

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