HSV-1 UL56 protein recruits cellular NEDD4-family ubiquitin ligases to suppress CD1d expression and NKT cell function

In the large DNA genomes of herpeviruses, there are many genes encoding associate proteins. Most of these proteins are not essential for viral replication but play key roles in viral pathogenesis, in particular, modulating the host immune system to allow efficient viral replication <i>in vivo</i> and latency. The HSV-1 UL56 gene is one of such genes, and its exact pathogenic roles have remain elusive. After we demonstrated the essential roles of CD1d-restricted NKT cells in anti-HSV-1 immunity during HSV-1 ocular infection (P. Rao, X. Wen, J. H. Lo, S. Kim, X. Li, et al., J Virol 92:e01490-18, 2018, https://doi.org/10.1128/jvi.01490-18), we now screened the HSV-1 expression library and identified UL56 is a key factor downregulating CD1d and suppressing NKT cell function. In this manuscript, we are reporting our molecular mechanism study of how UL56 evades CD1d antigen presentation and NKT cell function.