Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7.
Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7.
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DOI：
10.1371/journal.ppat.1009179
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发表时间：
2021-01
期刊：
影响因子：
6.7
通讯作者：
Lee HR
中科院分区：
文献类型：
--
作者：
Kim YJ;Kim Y;Kumar A;Kim CW;Toth Z;Cho NH;Lee HR
原发性渗出性淋巴瘤（PEL）是一种侵袭性B细胞淋巴瘤，其病因与卡波西肉瘤相关疱疹病毒（KSHV）有关。尽管进行了标准的多种化疗治疗，但PEL仍然导致高死亡率。因此，迫切需要新的策略来控制PEL。在这里，我们表明，磷酸降解基序内的KSHV蛋白，潜伏相关的核抗原（拉娜），特异性地与E3泛素连接酶FBW 7相互作用，从而竞争性地抑制结合的抗凋亡蛋白MCL-1 FBW 7。因此，LANA-FBW 7相互作用通过防止MCL-1的蛋白酶体介导的降解来增强其稳定性，这抑制了PEL细胞中caspase-3介导的凋亡。重要的是，MCL-1抑制剂显著抑制软琼脂上的集落形成和异种移植小鼠模型中KSHV+PEL/BCBL-1的肿瘤生长。这些结果有力地支持了以下结论：高水平的MCL-1表达能够使PEL细胞发生肿瘤，因此，MCL-1可能是KSHV相关PEL的潜在药物靶点。这项工作还揭示了致癌病毒干扰泛素化途径的关键组分以诱导肿瘤发生的机制。原发性渗出性淋巴瘤（PEL）是一种高度侵袭性的B细胞淋巴瘤，与卡波西肉瘤相关疱疹病毒（KSHV）有关。然而，KSHV相关的PEL的侵略性管理的潜在机制知之甚少。在这里，我们证明了KSHV拉娜与细胞泛素E3连接酶FBW 7相互作用，将MCL-1与FBW 7隔离，从而减少MCL-1的泛素化。因此，拉娜有效地稳定和增加MCL-1蛋白，导致抑制PEL细胞中半胱天冬酶-3介导的细胞凋亡。此外，MCL-1抑制剂在小鼠异种移植模型中有效阻断PEL进展。这些结果表明，拉娜作为一个原癌基因通过去调节肿瘤抑制因子FBW 7，上调抗凋亡MCL-1的表达。这项研究表明，靶向MCL-1的药物可以作为一种有效的治疗KSHV+ PEL。
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. 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.
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