Intrinsic immunity against HAdV is achieved by a novel epigenetic silencing complex

The DNA double-stranded genome of human adenoviruses (HAdV) is preferentially targeted by host factors involved in chromatin remodeling, such as SPOC1 and KAP1 to inhibit efficient viral gene expression. HAdV genomes undergo alterations through association with host histones and epigenetic modifications; however, the precise underlying mechanism remains elusive. A recently discovered silencing mechanism for retrotransposons and retroviruses involves the Human Silencing Hub (HUSH) complex. This complex of MPP8, TASOR, and PPHLN1 safeguards the human genome by utilizing histone H3 Lys9 trimethylation (H3K9me3) to block transcription. Through the recruitment of SETDB1 and MORC2, the HUSH complex silences host genes and condenses target genomes to combat infections such as HIV, MLV, and AAV. Here, we present evidence that the HUSH complex effectively restricts HAdV infection. To counteract the repressive function of this epigenetic silencing complex, HUSH factors are inhibited through binding of HAdV proteins and subsequent relocalization. We observe that MPP8 is targeted by the adenoviral E3 ubiquitin ligase, thus recruited by the viral early proteins E1B-55K and E4orf6 for proteasomal degradation. In summary, we provide evidence that the HUSH complex is a previously unrecognized host factor that restricts HAdV gene expression and replication. Based on these novel findings, we propose that HUSH represents a promising therapeutic target to combat HAdV infection.