Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7

Abstract

Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma that is etiologically linked to Kaposi's sarcoma-associated herpesvirus (KSHV). Despite standard multi-chemotherapy treatment, PEL continues to cause high mortality. Thus, new strategies to control PEL are needed urgently. Here, we show that a phosphodegron motif within the KSHV protein, latency-associated nuclear antigen (LANA), specifically interacts with E3 ubiquitin ligase FBW7, thereby competitively inhibiting the binding of the anti-apoptotic protein MCL-1 to FBW7. Consequently, LANA-FBW7 interaction enhances the stability of MCL-1 by preventing its proteasome-mediated degradation, which inhibits caspase-3-mediated apoptosis in PEL cells. Importantly, MCL-1 inhibitors markedly suppress colony formation on soft agar and tumor growth of KSHV+PEL/BCBL-1 in a xenograft mouse model. These results strongly support the conclusion that high levels of MCL-1 expression enable the oncogenesis of PEL cells and thus, MCL-1 could be a potential drug target for KSHV-associated PEL. This work also unravels a mechanism by which an oncogenic virus perturbs a key component of the ubiquitination pathway to induce tumorigenesis. Author summary Primary effusion lymphoma (PEL), a highly aggressive B cell lymphoma, is associated with Kaposi's sarcoma-associated herpesvirus (KSHV). However, the underlying mechanisms that govern the aggressiveness of KSHV-associated PEL are poorly understood. Here, we demonstrate that KSHV LANA interacts with cellular ubiquitin E3 ligase FBW7, sequestering MCL-1 from FBW7, which reduces MCL-1 ubiquitination. As such, LANA potently stabilizes and increases MCL-1 protein, leading to inhibition of caspase-3-mediated apoptosis in PEL cells. Furthermore, MCL-1 inhibitors efficiently blocked PEL progression in mouse xenograft model. These results suggest that LANA acts as a proto-oncogene via deregulating tumor suppressor FBW7, which upregulates anti-apoptotic MCL-1 expression. This study suggests drugs that target MCL-1 may serve as an effective therapy against KSHV+ PEL.