Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias.
Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias.
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DOI：
10.1158/0008-5472.can-08-3735
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Young HA
中科院分区：
文献类型：
--
作者：
Hodge DL;Yang J;Buschman MD;Schaughency PM;Dang H;Bere W;Yang Y;Savan R;Subleski JJ;Yin XM;Loughran TP Jr;Young HA
大颗粒淋巴细胞白血病是一种T细胞和自然杀伤细胞的克隆性增生性疾病。IL-15在LGL白血病的发生发展中起重要作用，是正常NK和T记忆细胞的生存因子。IL-15可改变BID中Bid、Bim、Noxa和Mcl-1等基因的表达，但对Bid的影响不明显。使用过继转移模型，我们发现，当将BID缺陷小鼠的NK细胞转移到IL-15缺失的小鼠中时，来自BID缺陷小鼠的NK细胞比来自野生型对照小鼠的细胞存活时间更长。在正常人NK细胞中，IL-15显著减少BID的蓄积。BID的减少不是由于RNA积累的改变，而是由于蛋白酶体降解增加所致。IL-15上调E3连接酶Hdm2，我们发现Hdm2直接与Bid相互作用。短发夹RNA对Hdm2的抑制增加了Bid的积累，进一步支持Hdm2参与BID降解。在原发白血病LGL中，BID水平很低，但经Bortezomib治疗后，LGL凋亡增加，BID水平被逆转。总之，这些数据为IL-15控制BID提供了一种新的分子机制，该机制可能通过BID的靶向蛋白酶体降解将该细胞因子与白血病的发生联系起来，并提供了蛋白酶体抑制剂可能有助于LGL白血病治疗的可能性。
Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15 is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15 alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1; however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Bid-deficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15 significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15 up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15 control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia.