UCLA

The gammaherpesviruses are unique in their oncogenic potential and their ability to establish lifelong infection. Their success results from a variety of delicate interactions with the natural hosts. In this thesis, we study the interaction between a host response termed the unfolded protein response (UPR) and infection of murine gammaherpesvirus 68 (MHV-68). MHV-68 is a model virus widely used to study the human gammaherpesviruses. UPR is triggered by accumulated unfolded proteins in the endoplasmic reticulum (ER) and activates a collection of signaling pathways (IRE1, ATF6, PERK) that can be beneficial or deleterious to viral replication. We found that cellular UPR is important for MHV-68 replication. The infection cycle of MHV-68 leads to a changing UPR in the host cells. Cellular UPR is inhibited at the early stages of infection and becomes upregulated later on.

To identify viral modulators of cellular UPR, an unbiased screen was conducted, uncovering M1 as a strong UPR inducer and ORF40 as an inhibitor. M1 is found to localize to the ER and markedly induces the production of ER chaperones. It selectively induces the chaperon-producing branches (IRE1, ATF6) while sparing the translation-blocking arm (PERK). On the other hand, the viral helicase-primase component ORF40 is capable of downregulating each UPR pathway. We provide evidence that ORF40 may function through binding to and stabilizing the inactive complexes of the transmembrane stress sensors and chaperones to prevent UPR initiation. Despite the seemingly contradictory effects of the two viral proteins, further investigation revealed distinct expression patterns of ORF40 and M1 genes. ORF40 is expressed at the early stages of virus infection while M1 peaks at later stages. Intriguingly, M1 is found to be able to interfere with the anti-UPR function of ORF40. These findings explain the dynamic modulation of cellular UPR by MHV-68 during infection with ORF40 functioning at the early stage and M1 at the late stages of viral life cycle.

Collectively, the delicate regulation of UPR by MHV-68 suggests this cellular response is crucial in controlling gammaherpesvirus infection. Further investigation on the molecular interaction between the virus and UPR may yield important information for developing new anti-viral therapies.