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.
Highlights
The ubiquitin-proteasome system (UPS) is a network of proteins involved in ubiquitination of cellular targets and subsequent control of numerous cellular functions
We demonstrate that Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) interacts with cellular ubiquitin E3 ligase F-box and WD repeat domain-containing 7 (FBW7), sequestering myeloid cell leukemia-1 (MCL-1) from FBW7, which reduces MCL-1 ubiquitination
While investigating the function of LANA, we identified two consensus Cdc4 phosphodegron (CPD) motifs in its N-terminal region (Fig 1A) that appear to be recognized by FBW7
Summary
The ubiquitin-proteasome system (UPS) is a network of proteins involved in ubiquitination of cellular targets and subsequent control of numerous cellular functions. Dysregulation of the components of this elaborate network leads to human diseases such as cancer [1]. One predominantly dysregulated component of UPS is an E3 ubiquitin ligase called F-box and WD repeat domain-containing 7 (FBW7) that recognizes phosphorylated substrates within the conserved Cdc phosphodegron (CPD) motif [2,3]. FBW7 has been classified as a tumor suppressor that induces degradation of several proto-oncogenes such as c-Myc, cyclin E, and myeloid cell leukemia-1 (MCL-1) [2,3,4]. MCL1 is frequently amplified or overexpressed in a broad spectrum of cancers to promote tumor cell survival, suggesting its oncogenic role [7,8]. MCL-1 is highly expressed in tissues from patients with primary effusion lymphoma (PEL) [9,10,11]
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