Characterizing the interactions between murine cytomegalovirus M72 and the carbon catabolite repression 4-negative on...

Despite being an important human pathogen, many Human cytomegalovirus (HCMV) gene products remain uncharacterized. The betaherpesvirus conserved core genes, UL72 from HCMV and M72, the murine cytomegalovirus (MCMV) homolog, were initially designated as the 2'-deoxyuridine 5'-triphosphate pyrophosphatase (dUTPase) homolog. However, other researchers and we have shown that both are non-essential for replication and lack dUTPase activity. Using a proteomics approach, we previously established a set of candidates of functionally interacting host proteins with M72. Among them, several subunits of the carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex were identified as likely functional interactors with M72. The CCR4-NOT complex is a multifunctional, heteromeric complex regarded as the main deadenylase in eukaryotic cells. Interactions between M72 and the CCR4-NOT complex were confirmed during infection and mapped. Here, we show that M72 binds to regions of CNOT1, the major scaffold and coordinator of the complex, which are responsible for recruiting the deadenylase subunits. We also reveal that M72 and CNOT1 are both required to augment normal MCMV replication. These results suggest a novel function for M72 in modulating the CCR4-NOT complex, as well as a pro-viral role for CNOT1 in MCMV pathogenesis.