ABHD11 mediated deglutarylation regulates the TCA cycle and T cell metabolism

Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity, exerting its effects by inhibition of histone demethylase enzymes or through glutarylation. However, how distinct glutarate modifications are regulated is unclear. Here, we uncover a deglutarylation pathway that couples amino acid catabolism to tricarboxylic acid (TCA) cycle function. By examining how glutarate can form conjugates with lipoate, an essential mitochondrial modification for the TCA cycle, we find that Alpha Beta Hydrolase Domain 11 (ABHD11) protects against the formation of glutaryl-lipoyl adducts. Mechanistically, ABHD11 acts as a thioesterase to selectively remove glutaryl adducts from lipoate, maintaining integrity of the TCA cycle. Functionally, ABHD11 influences the metabolic reprogramming of human T cells, increasing central memory T cell formation and attenuating oxidative phosphorylation. These results uncover ABHD11 as a selective deglutarylating enzyme and highlight that targeting ABHD11 offers a potential approach to metabolically reprogramme cytotoxic T cells. Activated CD8+ T cells were cultured in complete RPMI 1640 supplemented with 10% FBS and 30 U/ml IL-2 and treated with 1 uM ML226 for 11 days.

戊二酸（Glutarate）是氨基酸分解代谢的中间产物，同时也是重编程T细胞免疫功能的重要代谢物，可通过抑制组蛋白去甲基化酶或发生戊二酰化修饰发挥生物学效应。然而，目前学界尚不清楚不同类型的戊二酸修饰是如何被调控的。本研究揭示了一条将氨基酸分解代谢与三羧酸（TCA）循环功能相偶联的去戊二酰化通路。通过探究戊二酸如何与硫辛酰基结合——硫辛酰基是TCA循环所必需的线粒体修饰——我们发现α/β水解酶结构域11（Alpha Beta Hydrolase Domain 11, ABHD11）可有效阻断戊二酰-硫辛酰基加合物的形成。机制研究表明，ABHD11作为硫酯酶，可选择性地从硫辛酰基上移除戊二酰加合物，从而维持TCA循环的结构完整性与功能稳定性。在细胞功能层面，ABHD11可调控人T细胞的代谢重编程，促进中枢记忆性T细胞的生成并减弱氧化磷酸化过程。上述研究结果将ABHD11鉴定为一种选择性去戊二酰化酶，并表明靶向ABHD11可为代谢重编程细胞毒性T细胞提供潜在的治疗策略。本实验中，活化的CD8+ T细胞在添加了10%胎牛血清（Fetal Bovine Serum, FBS）与30 U/ml白细胞介素-2（Interleukin-2, IL-2）的完全RPMI 1640培养基中培养，并以1 μM ML226处理11天。