ViHiHippo · Viral hijacking of the Hippo pathway - HCMV-encoded viral GPCRs US28 and UL78 differentially modulate the Hippo pathway in cancer.

The human cytomegalovirus (HCMV) is a herpesvirus that infects large parts of the population, with a prevalence of 80-100% in Europe. In healthy individuals, HCMV infection usually induces little to no symptoms. However, recent findings indicate that HCMV might contribute to a variety of diseases, including cancer and heart disease, two of the leading causes of death in Europe. The aim of this project is to uncover how and why HCMV changes the progression of cancer. To achieve this, we will investigate two HCMV-encoded viral G protein-coupled receptors (vGPCRs), US28 and UL78. Like other viral proteins, these vGPCRs hijack the signaling network of the host cell. Specifically, US28 and UL78 modulate the Hippo pathway, which controls cell proliferation and organ growth. As dysregulation of the Hippo pathway has been linked to cancer, modulation of this pathway by these vGPCRs may be a crucial determinant of HCMV on cancer progression. Our preliminary findings show that US28 and UL78 activate distinct mechanisms to hijack the Hippo pathway. US28 couples to G proteins of the Gq/G12 family, which are known to lead to Hippo modulation. Conversely, UL78 does not signal to Gq/G12, and seems to hijack the Hippo pathway via a different, undescribed mechanism. Thus, we will use a combination of biochemical readouts to investigate the signaling of US28- and UL78-expressing cells, to identify the distinct signaling mechanisms by which each vGPCR hijacks the Hippo pathway. We will also investigate the outcomes of this Hippo pathway modulation in a viral cancer setting by infecting a glioblastoma cell line with HCMV strains that either encode or lack US28 or UL78. Our findings will contribute to a fundamental understanding of how HCMV can influence progression of cancer. Moreover, these studies might potentially identify a new mechanism linking GPCRs to cell proliferation. In the long term this project may lay the groundwork for the discovery of new cancer treatments.