HCMV UL148 and UL148D regulate multiple immune pathways by impairing expression of ADAM17

Human cytomegalovirus (HCMV) is one of the most widespread, highly successful herpesviruses, establishing a life-long viral infection in humans. HCMV has been described as a paradigm of immune evasion able to manipulate many immune functions in the host. Here, we describe a novel, post-translational mechanism in which HCMV downregulates a disintegrin and metalloproteinase 17 (ADAM17), a ‘sheddase’ that cleaves and releases over 80 membrane-anchored cytokines, cell adhesion molecules and other receptors. A screen of HCMV deletion mutants identified UL148 and UL148D as the HCMV genes responsible for ADAM17 downregulation, working synergistically to alter ADAM17 levels in infected cells. We demonstrate that UL148/UL148D interfere with ADAM17 maturation, resulting in expression of only the intracellular immature precursor, and absence of mature ADAM17 on the surface of wildtype HCMV-infected cells. The consequences of ADAM17 downregulation by HCMV were analysed using proteomics and validated using biochemical and flow cytometric techniques, revealing impact on multiple cell surface and secreted host proteins. This included stabilisation of surface TNF Receptor 2, as well as Vasorin and Jagged1, which have recognised roles in Treg development. Other known ADAM17 targets were not stabilised, suggesting specific control by HCMV. Vaccinia virus, another paradigm of immune evasion, also impaired surface ADAM17 expression, suggesting that manipulation of ADAM17 may represent a novel immunoregulatory hub targeted by large DNA viruses.