Human cytomegalovirus pUS22: a novel transcriptional inhibitor that represses cellular necroptosis.

Human cytomegalovirus (HCMV) is an important human pathogen and paradigm for subversion of host intrinsic, innate, and adaptive immunity. Necroptosis is a critical intrinsic antiviral defence that directly eliminates infected cells, preventing viral spread. However, a systematic analysis to comprehensively identify HCMV necroptosis antagonists is lacking. Here, we screened HCMV block deletion viruses lacking clusters of ‘accessory’ genes non-essential for viral replication, cell lines stably expressing individual genes in the candidate block, and single-gene deletion viral mutants. This identified pUS22 as a novel necroptosis inhibitor and the first viral protein to repress transcription of the key necrosome component RIPK3. pUS22 sequesters transcription factors Sp1 and Sp3, which would otherwise activate RIPK3 transcription by binding a core proximal promoter element. As a consequence of reduced RIPK3 protein abundance, phosphorylation of terminal necroptosis mediator MLKL is inhibited, limiting cell death and enhancing viral replication and spread.