Adriana Ramirez Negron

UC Santa Barbara

Exploring the role of activating transcription factor 6 in Kaposi’s sarcoma-associated herpesvirus infection

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus, known to cause malignancies in immunocompromised patients. To gain control of the host protein folding machinery during infection, KSHV modulates the unfolded protein response (UPR), but the precise mechanisms it uses to do so remain unknown. The UPR is a cellular homeostatic mechanism that alleviates stress in the endoplasmic reticulum(ER) when unfolded proteins accumulate. The UPR consists of three protein signal transducers: IRE1, PERK, and ATF6. KSHV inhibits the signaling of IRE1 and PERK in infected cells preventing their normal function, but how it controls ATF6 remains unclear. In this project, we focused on exploring the role of ATF6 in KSHV infection. In our initial approach, we treated KSHV-latently infected cells with Ceapin, a small molecule that inhibits ATF6 function by sequestering this transcription factor in the cytoplasm of the cell. We tested if Ceapin worked in these infected cells by determining the protein levels of the ER-chaperon BiP by immunoblot. BiP is an important chaperone that is transcriptionally regulated by ATF6 in response to ER stress. Our results indicate that Ceapin worked since it prevented the upregulation of BiP in ER stress induced-cells. We are currently testing the effect of ATF6 on KSHV protein expression and virus replication. Our project will help better understand virus-host interactions anduncover potential targets for the development of future therapies.

NIH UC Santa Barbara Center for Science and Engineering Partnerships UCSB California NanoSystems Institute MCDB