TBC1D23 mediates Golgi-specific LKB1 signaling

Yingfeng Tu, Qin Yang, Min Tang, Li Gao, Yuanhao Wang, Jiuqiang Wang, Zhe Liu, Xiaoyu Li, Lejiao Mao, Rui zhen Jia, Yuan Wang, Tie-shan Tang, Pinglong Xu, Yan Liu, Lunzhi Dai and Da Jia ()
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Yingfeng Tu: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University
Qin Yang: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University
Min Tang: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University
Li Gao: Sichuan University
Yuanhao Wang: Nanjing Medical University
Jiuqiang Wang: Chinese Academy of Sciences
Zhe Liu: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University
Xiaoyu Li: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University
Lejiao Mao: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University
Rui zhen Jia: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University
Yuan Wang: Sichuan University
Tie-shan Tang: Chinese Academy of Sciences
Pinglong Xu: Zhejiang University
Yan Liu: Nanjing Medical University
Lunzhi Dai: Sichuan University
Da Jia: West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, and energy homeostasis. Functions and mechanisms of the LKB1-AMPK axis at specific subcellular compartments, such as lysosome and mitochondria, have been established. AMPK is known to be activated at the Golgi; however, functions and regulatory mechanisms of the LKB1-AMPK axis at the Golgi apparatus remain elusive. Here, we show that TBC1D23, a Golgi-localized protein that is frequently mutated in the neurodevelopment disorder pontocerebellar hypoplasia (PCH), is specifically required for the LKB1 signaling at the Golgi. TBC1D23 directly interacts with LKB1 and recruits LKB1 to Golgi, promoting Golgi-specific activation of AMPK upon energy stress. Notably, Golgi-targeted expression of LKB1 rescues TBC1D23 deficiency in zebrafish models. Furthermore, the loss of LKB1 causes neurodevelopmental abnormalities in zebrafish, which partially recapitulates defects in TBC1D23-deficient zebrafish, and LKB1 sustains normal neuronal development via TBC1D23 interaction. Our study uncovers a regulatory mechanism of the LKB1 signaling, and reveals that a disrupted Golgi-LKB1 signaling underlies the pathogenesis of PCH.

Date: 2024
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DOI: 10.1038/s41467-024-46166-2

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