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Activation of Mevalonate Pathway Via LKB1 is Essential for Stability of Treg Cells

67 Pages Posted: 26 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Maheshwor Timilshina

Maheshwor Timilshina

Yeungnam University - College of Pharmacy

Zhiwei You

Yeungnam University - College of Pharmacy

Sonja M. Lacher

Johannes Gutenberg University Mainz - Institute for Molecular Medicine

Suman Acharya

Yeungnam University - College of Pharmacy

Liyuan Jiang

Yeungnam University - College of Pharmacy

Youra Kang

Yeungnam University - College of Pharmacy

Jung-Ae Kim

Yeungnam University - College of Pharmacy

Hyeun Wook Chang

Yeungnam University - College of Pharmacy

Keuk-Jun Kim

Daekyeung College - Department of Biomedical Laboratory Science

Byoungduck Park

Keimyung University - College of Pharmacy

Jae-Hyoung Song

Kangwon National University - Laboratory of Microbiology and Immunology

Hyun-Jeong Ko

Kangwon National University - Laboratory of Microbiology and Immunology

Yun-Yong Park

University of Ulsan - Asan Institute for Life Sciences

Min-Jung Ma

Daegu-Gyeongbuk Medical Innovation Foundation - New Drug Development Center

Mahesh Raj Nepal

Yeungnam University - College of Pharmacy

Tae Cheon Jeong

Yeungnam University - College of Pharmacy

Yeonseok Chung

Seoul National University - Research Institute of Pharmaceutical Science

Ari Waisman

Johannes Gutenberg University Mainz - Institute for Molecular Medicine

Jae-Hoon Chang

Yeungnam University - College of Pharmacy

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Abstract

The function of Foxp3+ regulatory T cells (Treg cells) depends on lipid oxidation. However, the molecular mechanism by which Treg cells maintain lipid metabolism after activation remains elusive. LKB1 serine/threonine kinase acts as a coordinator of metabolism by linking cellular metabolism to the substrate AMP-activated protein kinase (AMPK). We found that mice with a conditional deletion of LKB1 in Treg cells developed a fatal autoimmune inflammation. LKB1-deficient Treg cells exhibited a reduced suppressive activity associated with effector T cell-like phenotypes. Mechanistically, LKB1 induced the activation of mevalonate pathway by up-regulating mevalonate genes in Treg cells independently of AMPK. LKB1-mediated mevalonate pathway was essential for Treg cell functional competency and stability by inducing Treg cell proliferation and by suppressing their IFN-γ and IL-17A expression. In agreement, mevalonate and its metabolite geranylgeranyl pyrophosphate (GGPP) not only inhibited the conversion of Treg cells to Th1- and Th17-like cells, but also enhanced the survival of LKB1-deficient Treg cells. Our results demonstrate that LKB1 is a key regulator of lipid metabolisms in Treg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.

Suggested Citation

Timilshina, Maheshwor and You, Zhiwei and Lacher, Sonja M. and Acharya, Suman and Jiang, Liyuan and Kang, Youra and Kim, Jung-Ae and Chang, Hyeun Wook and Kim, Keuk-Jun and Park, Byoungduck and Song, Jae-Hyoung and Ko, Hyun-Jeong and Park, Yun-Yong and Ma, Min-Jung and Nepal, Mahesh Raj and Jeong, Tae Cheon and Chung, Yeonseok and Waisman, Ari and Chang, Jae-Hoon, Activation of Mevalonate Pathway Via LKB1 is Essential for Stability of Treg Cells (January 9, 2019). Available at SSRN: https://ssrn.com/abstract=3312731 or http://dx.doi.org/10.2139/ssrn.3312731
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Maheshwor Timilshina

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Zhiwei You

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Sonja M. Lacher

Johannes Gutenberg University Mainz - Institute for Molecular Medicine

Langenbeckstraße 1
Mainz, 55131
Germany

Suman Acharya

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Liyuan Jiang

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Youra Kang

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Jung-Ae Kim

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Hyeun Wook Chang

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Keuk-Jun Kim

Daekyeung College - Department of Biomedical Laboratory Science

Gyeongsan 38547
Korea, Republic of (South Korea)

Byoungduck Park

Keimyung University - College of Pharmacy

Dalseo-Gu, Daegu 704-701
Korea, Republic of (South Korea)

Jae-Hyoung Song

Kangwon National University - Laboratory of Microbiology and Immunology

Chunchon
Korea, Republic of (South Korea)

Hyun-Jeong Ko

Kangwon National University - Laboratory of Microbiology and Immunology

Chunchon
Korea, Republic of (South Korea)

Yun-Yong Park

University of Ulsan - Asan Institute for Life Sciences

Seoul, 05505
Korea, Republic of (South Korea)

Min-Jung Ma

Daegu-Gyeongbuk Medical Innovation Foundation - New Drug Development Center

Daegu, 41061
Korea, Republic of (South Korea)

Mahesh Raj Nepal

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Tae Cheon Jeong

Yeungnam University - College of Pharmacy

Kyongsan, 712-749
Korea, Republic of (South Korea)

Yeonseok Chung

Seoul National University - Research Institute of Pharmaceutical Science

Kwanak-gu
Seoul, 151-742
Korea, Republic of (South Korea)

Ari Waisman

Johannes Gutenberg University Mainz - Institute for Molecular Medicine ( email )

Langenbeckstraße 1
Mainz, 55131
Germany

Jae-Hoon Chang (Contact Author)

Yeungnam University - College of Pharmacy ( email )

Kyongsan, 712-749
Korea, Republic of (South Korea)

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