Downregulation of MHC class I molecules by herpesviruses: Usurpation of intracellular trafficking pathways

Herpesviruses remain in their host for life by establishing latency after acute infection. Downregulation of intracellular antigen presentation to the immune system by herpesviruses is thought to play a key role in establishment of latency and persistence. In many cases, the virus appropriates cellular machinery that is involved in intracellular trafficking pathways and converts it in a targeting pathway for MHC class I complex destruction. This dissertation focuses on three herpesvirus gene products, Kaposi's sarcoma-associated herpesvirus K3 and human cytomegalovirus US2 and US11, that have co-opted the existing cellular machinery involved in intracellular protein trafficking for the purpose of MHC I destruction. K3-mediated downregulation of MHC I from the plasma membrane can be dissected into at least two independent steps, internalization and ubiquitin-proteasome system-dependent sorting into late endocytic compartments. This highlights that internalization of proteins and downstream sorting can be independently regulated steps. N-terminal ubiquitination of K3 might help us understand the role of polyubiquitin and proteasomal activity in protein internalization and downstream sorting. The attempt to reconstitute US2 and US11 mediated dislocation of MHC I heavy chain in yeast has underscored the complexity of the ER quality control pathways and the dependence of these viral proteins on the cellular machinery. Finally, US2 has shed light on the process of targeting and translocation of proteins into the ER and their regulation by the unfolded protein response. These studies not only provide understanding of the viral strategy of immune evasion, but also elucidate details of the cell biology and biochemistry of the involved trafficking pathway.