TBC1D23 mediates Golgi-specific LKB1 signaling

• Published in: Nature communications Vol. 15; no. 1; p. 1785
• Main Authors: Tu, Yingfeng, Yang, Qin, Tang, Min, Gao, Li, Wang, Yuanhao, Wang, Jiuqiang, Liu, Zhe, Li, Xiaoyu, Mao, Lejiao, Jia, Rui zhen, Wang, Yuan, Tang, Tie-shan, Xu, Pinglong, Liu, Yan, Dai, Lunzhi, Jia, Da
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 13; 13/1; 13/95; 14/33; 14/35; 631/378/2571; 631/80/642/1525; 631/80/86; 64/116; 82/83; Abnormalities; Compartments; Danio rerio; Energy balance; Golgi apparatus; Homeostasis; Humanities and Social Sciences; Hypoplasia; Kinases; LKB1 protein; multidisciplinary; Neurodevelopment; Neurodevelopmental disorders; Pathogenesis; Protein-serine/threonine kinase; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46166-2

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. The LKB1 signaling is differentially regulated and has distinct functions at different subcellular compartments. Tu et al reports that TBC1D23 specifically regulates Golgi-LKB1 signaling and link this pathway to neurodevelopment disorders.