Modulation of immunity by viral regulation of cellular PP1

The addition or elimination of phosphates on proteins of the cell are important mechanisms to regulate (activate or inhibit) the function of enzymes in human cells. For this purpose, cells use protein kinases (PK) and protein phosphatases (PP) to add or remove phosphorylations on proteins. More than 70% of all human cellular proteins are regulated by this mechanism of protein phosphorylation. Several viruses exploit the importance of this mechanism for the host cell for the benefit of viral replication. Viruses may express viral analogs of proteins that down-regulate the activity of these enzymes by binding phosphatases, inhibit the activity of the enzymes directly, or use the enzymes as shuttle to the nucleus of cells. In contrast, human Cytomegalovirus (CMV) activates phosphatases in human cells and carries additionally cellular protein phosphatase 1 (PP1) in its virion for a rapid supply of the enzyme after viral entry. Surprisingly, PP1 activity seems to be required for optimal CMV replication. The aim of the present study is the elucidation of this seemingly conflicting evidence by testing cellular mechanisms involved in the regulation of a phosphatase critical for the virus and the cell. For this purpose, we will (1) define the viral interaction partner of PP1 using methods that identify the interaction between proteins; (2) evaluate if and at what point in the viral life cycle inhibition of PP1 could be antiviral, including validation experiments in vivo; (3) define the consequences of CMV-imported PP1 on the innate immune system. The study will give important insights into how CMV uses human phosphatases for its own benefit. A better understanding of cellular phosphorylation and antiviral responses will be of high clinical relevance for the identification of novel antiviral drugs.