6533b822fe1ef96bd127cd45
RESEARCH PRODUCT
Activation of Mevalonate Pathway Via LKB1 is Essential for Stability of Treg Cells
Keuk-jun KimHyeun Wook ChangHyun-jeong KoMin-jung MaMaheshwor TimilshinaTae Cheon JeongYeonseok ChungJae-hyoung SongMahesh Raj NepalJung-ae KimJae-hoon ChangYoura KangLiyuan JiangYun-yong ParkSonja M. LacherAri WaismanByoungduck ParkZhiwei YouSuman Acharyasubject
0301 basic medicinecongenital hereditary and neonatal diseases and abnormalitiesGeranylgeranyl pyrophosphateKinaseAMPKFOXP3hemic and immune systemschemical and pharmacologic phenomenaLipid metabolismGeneral Biochemistry Genetics and Molecular BiologyCell biology03 medical and health scienceschemistry.chemical_compound030104 developmental biology0302 clinical medicinelcsh:Biology (General)chemistryLipid oxidationMevalonate pathwayskin and connective tissue diseasesProtein kinase Alcsh:QH301-705.5030217 neurology & neurosurgeryHomeostasisdescription
Summary: 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. : Timilshina et al. show that the LKB1-mediated mevalonate pathway is required for proper function and stability of Treg cells. These data provide mechanistic insight into the lipid metabolic programs that promote immune homeostasis and tolerance and suggest that lipid metabolism is a possible therapeutic target for pharmacological manipulation of Treg biology. Keywords: LKB1, Treg cells, mevalonate pathway, Treg stability, GGPP, autoimmune disease
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-06-01 | SSRN Electronic Journal |