Varicella-zoster virus IE62 protein utilizes the human mediator complex in promoter activation

The varicella-zoster virus (VZV) major transactivator, IE62, is involved in the expression of all kinetic classes of VZV genes and can also activate cellular promoters, promoters from heterologous viruses, and artificial promoters containing only TATA elements. A key component of the mechanism of IE62 transactivation is an acidic activation domain comprising the N-terminal 86 amino acids of IE62. However, the cellular target of this N-terminal acidic activation is unknown. In the work presented here, we show that the IE62 activation domain targets the human Mediator complex via the Med25 (ARC92) subunit and that this interaction appears to be fundamental for transactivation by the IE62 activation domain. In contrast, the Med23 subunit (Sur2/TRAP150beta/DRIP130/CRSP130) of the Mediator complex is not essential for IE62-mediated activation. Further, the IE62 activation domain appears to selectively interact with a form of the Mediator complex lacking CDK8. Chromatin immunoprecipitation experiments showed that IE62 stimulates recruitment of Mediator to an IE62-responsive model promoter. Finally, immunofluorescence microscopy of VZV-infected cells demonstrated intranuclear translocation of the Mediator complex to viral replication compartments. These studies suggest that Mediator is an essential component for efficient VZV gene expression.     

Med1 controls CD8 T cell maintenance through IL-7R-mediated cell survival signalling

Under steady-state conditions, the pool size of peripheral CD8⁺ T cells is maintained through turnover and survival. Beyond TCR and IL-7R signals, the underlying mechanisms are less well understood. In the present study, we found a significant reduction of CD8⁺ T cell proportion in spleens but not in thymi of mice with T cell-specific deletion of Mediator Subunit 1 (Med1). A competitive transfer of wild-type (WT) and Med1-deficient CD8⁺ T cells reproduced the phenotype in the same recipients and confirmed intrinsic role of Med1. Furthermore, we observed a comparable degree of migration and proliferation but a significant increase of cell death in Med1-deficient CD8⁺ T cells compared with WT counterparts. Finally, Med1-deficient CD8⁺ T cells exhibited a decreased expression of interleukin-7 receptor α (IL-7Rα), down-regulation of phosphorylated-STAT5 (pSTAT5) and Bim up-regulation. Collectively, our study reveals a novel role of Med1 in the maintenance of CD8⁺ T cells through IL-7Rα/STAT5 pathway-mediated cell survival.