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Activation of Mevalonate Pathway via LKB1 Is Essential for Stability of Treg Cells.
Cell Reports ( IF 7.5 ) Pub Date : 2019-06-04 , DOI: 10.1016/j.celrep.2019.05.020 Maheshwor Timilshina 1 , Zhiwei You 1 , Sonja M Lacher 2 , Suman Acharya 1 , Liyuan Jiang 1 , Youra Kang 1 , Jung-Ae Kim 1 , Hyeun Wook Chang 1 , Keuk-Jun Kim 3 , Byoungduck Park 4 , Jae-Hyoung Song 5 , Hyun-Jeong Ko 5 , Yun-Yong Park 6 , Min-Jung Ma 7 , Mahesh Raj Nepal 1 , Tae Cheon Jeong 1 , Yeonseok Chung 8 , Ari Waisman 2 , Jae-Hoon Chang 1
Cell Reports ( IF 7.5 ) Pub Date : 2019-06-04 , DOI: 10.1016/j.celrep.2019.05.020 Maheshwor Timilshina 1 , Zhiwei You 1 , Sonja M Lacher 2 , Suman Acharya 1 , Liyuan Jiang 1 , Youra Kang 1 , Jung-Ae Kim 1 , Hyeun Wook Chang 1 , Keuk-Jun Kim 3 , Byoungduck Park 4 , Jae-Hyoung Song 5 , Hyun-Jeong Ko 5 , Yun-Yong Park 6 , Min-Jung Ma 7 , Mahesh Raj Nepal 1 , Tae Cheon Jeong 1 , Yeonseok Chung 8 , Ari Waisman 2 , Jae-Hoon Chang 1
Affiliation
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The function of regulatory T (Treg) cells depends on lipid oxidation. However, the molecular mechanism by which Treg cells maintain lipid metabolism after activation remains elusive. Liver kinase B1 (LKB1) acts as a coordinator by linking cellular metabolism to substrate AMP-activated protein kinase (AMPK). We show that deletion of LKB1 in Treg cells exhibited reduced suppressive activity and developed fatal autoimmune inflammation. Mechanistically, LKB1 induced activation of the mevalonate pathway by upregulating mevalonate genes, which was essential for Treg cell functional competency and stability by inducing Treg cell proliferation and suppressing interferon-gamma and interleukin-17A expression independently of AMPK. Furthermore, LKB1 was found to regulate intracellular cholesterol homeostasis and to promote the mevalonate pathway. In agreement, mevalonate and its metabolite geranylgeranyl pyrophosphate inhibited conversion of Treg cells and enhanced survival of LKB1-deficient Treg mice. Thus, LKB1 is a key regulator of lipid metabolism in Treg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.
中文翻译：
通过LKB1激活甲羟戊酸途径对于Treg细胞的稳定性至关重要。
调节性T（Treg）细胞的功能取决于脂质氧化。然而，激活后Treg细胞维持脂质代谢的分子机制仍然难以捉摸。肝激酶B1（LKB1）通过将细胞的新陈代谢与底物AMP激活的蛋白激酶（AMPK）联系起来，起着协调器的作用。我们表明删除Treg细胞中的LKB1表现出降低的抑制活性和发展致命的自身免疫炎症。从机制上讲，LKB1通过上调甲羟戊酸基因来诱导甲羟戊酸途径的激活，这对Treg细胞功能能力和稳定性至关重要，其通过诱导Treg细胞增殖并抑制干扰素-γ和白介素17A的表达而独立于AMPK。此外，发现LKB1调节细胞内胆固醇稳态并促进甲羟戊酸途径。一致的是，甲羟戊酸及其代谢产物香叶基香叶基香叶基焦磷酸可抑制Treg细胞的转化并提高LKB1缺陷型Treg小鼠的存活率。因此，LKB1是Treg细胞中脂质代谢的关键调节剂，参与了抑制活性，免疫稳态和耐受性的最佳编程。
更新日期：2019-06-04
中文翻译：
通过LKB1激活甲羟戊酸途径对于Treg细胞的稳定性至关重要。
调节性T（Treg）细胞的功能取决于脂质氧化。然而，激活后Treg细胞维持脂质代谢的分子机制仍然难以捉摸。肝激酶B1（LKB1）通过将细胞的新陈代谢与底物AMP激活的蛋白激酶（AMPK）联系起来，起着协调器的作用。我们表明删除Treg细胞中的LKB1表现出降低的抑制活性和发展致命的自身免疫炎症。从机制上讲，LKB1通过上调甲羟戊酸基因来诱导甲羟戊酸途径的激活，这对Treg细胞功能能力和稳定性至关重要，其通过诱导Treg细胞增殖并抑制干扰素-γ和白介素17A的表达而独立于AMPK。此外，发现LKB1调节细胞内胆固醇稳态并促进甲羟戊酸途径。一致的是，甲羟戊酸及其代谢产物香叶基香叶基香叶基焦磷酸可抑制Treg细胞的转化并提高LKB1缺陷型Treg小鼠的存活率。因此，LKB1是Treg细胞中脂质代谢的关键调节剂，参与了抑制活性，免疫稳态和耐受性的最佳编程。
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