A role for MALT1 activity in Kaposi's sarcoma-associated herpes virus latency and growth of primary effusion lymphoma.
A role for MALT1 activity in Kaposi's sarcoma-associated herpes virus latency and growth of primary effusion lymphoma.
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MALT1 活性在卡波西肉瘤相关疱疹病毒潜伏期和原发性渗出性淋巴瘤生长中的作用
DOI：
10.1038/leu.2016.239
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发表时间：
2017-03
期刊：
影响因子：
11.4
通讯作者：
Thome M
中科院分区：
文献类型：
--
作者：
Bonsignore L;Passelli K;Pelzer C;Perroud M;Konrad A;Thurau M;Stürzl M;Dai L;Trillo-Tinoco J;Del Valle L;Qin Z;Thome M
原发性渗出性淋巴瘤（PEL）是一种无法治愈的恶性肿瘤，发生于免疫缺陷患者，是B细胞潜伏感染卡波西肉瘤相关疱疹病毒（KSHV）的结果。KSHV感染的B细胞的恶性生长需要转录因子核因子（NF）-κB的活性，其控制病毒潜伏期的维持和病毒裂解程序的抑制。我们发现KSHV蛋白K13和K15通过蛋白酶粘膜相关淋巴组织淋巴瘤易位蛋白1（MALT 1）促进NF-κB活化，MALT 1是淋巴细胞中NF-κB活化的关键驱动因子。MALT 1蛋白酶活性的抑制诱导病毒感染从潜伏期到裂解期的转变，并导致体外和异种移植模型中PEL细胞系的生长和存活减少。这些结果证明了MALT 1的蛋白水解活性在PEL中的关键作用，并为MEL治疗中MALT 1的药理学靶向提供了理论基础。
Primary effusion lymphoma (PEL) is an incurable malignancy that develops in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpes virus (KSHV). Malignant growth of KSHV-infected B cells requires the activity of the transcription factor nuclear factor (NF)-κB, which controls maintenance of viral latency and suppression of the viral lytic program. Here we show that the KSHV proteins K13 and K15 promote NF-κB activation via the protease mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), a key driver of NF-κB activation in lymphocytes. Inhibition of the MALT1 protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALT1 in PEL, and provide a rationale for the pharmacological targeting of MALT1 in PEL therapy.