The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression
The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression
复制标题
丝氨酸/苏氨酸激酶 LKB1 通过调节 AMPK 激活和 Bcl-XL 表达来控制胸腺细胞存活
DOI：
10.1038/cr.2009.141
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发表时间：
2010-01-01
期刊：
影响因子：
44.1
通讯作者：
Liu, Xiaolong
中科院分区：
文献类型：
--
作者：
Cao, Yonghao;Li, Hai;Liu, Xiaolong
LKB 1是一种丝氨酸/苏氨酸激酶，在生物能量应激时直接激活能量传感器AMP激活蛋白激酶（AMPK），主要作为控制细胞极性和增殖的肿瘤抑制因子。虽然LKB 1在包括胸腺和脾脏在内的多种组织中表达，但其在T细胞发育和功能中的作用仍然未知。在这里，我们表明，T细胞特异性LKB 1缺失导致双阳性（DP）胸腺细胞的存活率降低，CD 4和CD 8单阳性胸腺细胞的产生受损。LKB 1的破坏不仅阻止AMPK的活化，而且还损害抗凋亡蛋白Bcl-XL的表达。重要的是，异位表达的Bcl-XL或组成型活性AMPK突变体显着拯救DP胸腺细胞从LKB 1缺陷诱导的细胞死亡。此外，异位表达的组成型活性AMPK突变体被发现恢复表达Bcl-XL在LKB 1缺陷的DP胸腺细胞。这些发现确定LKB 1作为DP胸腺细胞通过调节AMPK活化和Bcl-XL表达而存活的关键因子。
LKB1 is a serine/threonine kinase that directly activates the energy sensor AMP-activated protein kinase (AMPK) in response to bioenergetic stress, and mainly acts as a tumor suppressor that controls cell polarity and proliferation. Although LKB1 is expressed in multiple tissues including the thymus and the spleen, its roles in T-cell development and function remain unknown. Here, we show that T-cell-specific deletion of LKB1 resulted in reduced survival of double-positive (DP) thymocytes and impaired generation of both CD4 and CD8 single-positive thymocytes. Disruption of LKB1 not only prevented the activation of AMPK but also impaired the expression of anti-apoptotic protein Bcl-XL. Importantly, ectopic expression of either Bcl-XL or the constitutively active AMPK mutant significantly rescued DP thymocytes from LKB1 deficiency-induced cell death. Moreover, ectopic expression of the constitutively active AMPK mutant was found to restore the expression of Bcl-XL in LKB1-deficient DP thymocytes. These findings identify LKB1 as a critical factor for the survival of DP thymocytes through regulation of AMPK activation and Bcl-XL expression.