Abstract

The genomes of human adenoviruses (HAdVs) are double-stranded DNA bound with viral nucleocapsid protein VII. During HAdV infection, host RNA polymerase can produce viral-associated RNAs (VA RNAs) that are recognized by retinoic acid-inducible gene I (RIG-I). However, it remains unclear whether and how HAdV, as a DNA virus, can evade RNA sensors. Here, we show that nucleocapsid protein VII from HAdV can inhibit type I interferon (IFN) production by antagonizing RIG-I. It is found that protein VII precursor of HAdV/C5 (C5preVII) could impede tripartite motif-containing protein 25 (TRIM25)-mediated K63 ubiquitination of RIG-I by preventing TRIM25 oligomerization. Importantly, we provide in vitro and in vivo evidence that cytoplasm-oriented C5preVII is responsible for TRIM25 inactivation. Moreover, the preVII proteins from diverse HAdVs show evolutionarily conserved immunosuppressive functions. Collectively, our study illustrates the function of HAdV preVII in retinoic acid-inducible gene I-like receptor (RLR) signaling and uncovers an evolutionally conserved mechanism of DNA viruses to evade host RNA sensors.