Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
复制标题
DOI：
10.1126/sciadv.adc9657
复制
发表时间：
2022-12-02
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
系统性红斑狼疮（SLE）是一种以调节性T细胞（Treg）缺陷为特征的自身免疫性疾病。在这里，我们证明了T细胞特异性的钙/钙调蛋白依赖性蛋白激酶4（CaMK 4）的缺失改善了B6.lpr狼疮易感小鼠的疾病，并扩大了Treg细胞。从机制上讲，CaMK 4磷酸化糖酵解限速酶6-磷酸果糖激酶，血小板型（PFKP），促进有氧糖酵解，而其最终产物果糖-1，6-二磷酸抑制氧化代谢。在Treg细胞中，CRISPR-Cas9使能的Pfkp缺失重现了Camk 4 −/− Treg细胞的代谢，并改善了它们在体外和体内的功能和稳定性。在SLE CD 4 + T细胞中，PFKP酶活性与SLE疾病活动和CaMK 4标准化PFKP活性的药理学抑制相关，导致Treg细胞功能增强。总之，我们提供了SLE中Treg细胞代谢和功能缺陷的分子见解，并将PFKP确定为微调Treg细胞代谢的靶点，从而恢复其功能。在自身免疫中，磷酸果糖激酶P重新连接Treg细胞代谢，导致免疫抑制功能和稳定性受损。
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) cells. Here, we demonstrate that a T cell–specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9–enabled Pfkp deletion recapitulated the metabolism of Camk4−/− Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function. In autoimmunity, phosphofructokinase P rewires Treg cell metabolism, leading to impaired immunosuppressive function and stability.
登录
查看更多内容
影响因子：
7.3
作者：
Ferretti AP;Bhargava R;Dahan S;Tsokos MG;Tsokos GC
通讯作者：
Tsokos GC
DOI：
10.1111/ajt.16140
发表时间：
2021-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Bhargava R;Maeda K;Tsokos MG;Pavlakis M;Stillman IE;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
4.9
作者：
Moulton VR;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
4.4
作者：
Kikawada, E;Lenda, DM;Kelley, VR
通讯作者：
Kelley, VR
影响因子：
4.4
作者：
Otomo, Kotaro;Koga, Tomohiro;Tsokos, George C.
通讯作者：
Tsokos, George C.