Lumenal Galectin-9-Lamp2 interaction regulates lysosome and autophagy to prevent pathogenesis in the intestine and pancreas

Janaki N. Sudhakar, Hsueh-Han Lu, Hung-Yu Chiang, Ching-Shu Suen, Ming-Jing Hwang, Sung-Yu Wu, Chia-Ning Shen, Yao-Ming Chang, Fu-An Li, Fu-Tong Liu and Jr-Wen Shui ()
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Janaki N. Sudhakar: Academia Sinica
Hsueh-Han Lu: Academia Sinica
Hung-Yu Chiang: Academia Sinica
Ching-Shu Suen: Academia Sinica
Ming-Jing Hwang: Academia Sinica
Sung-Yu Wu: Academia Sinica
Chia-Ning Shen: Academia Sinica
Yao-Ming Chang: Academia Sinica
Fu-An Li: Academia Sinica
Fu-Tong Liu: Academia Sinica
Jr-Wen Shui: Academia Sinica

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Intracellular galectins are carbohydrate-binding proteins capable of sensing and repairing damaged lysosomes. As in the physiological conditions glycosylated moieties are mostly in the lysosomal lumen but not cytosol, it is unclear whether galectins reside in lysosomes, bind to glycosylated proteins, and regulate lysosome functions. Here, we show in gut epithelial cells, galectin-9 is enriched in lysosomes and predominantly binds to lysosome-associated membrane protein 2 (Lamp2) in a Asn(N)-glycan dependent manner. At the steady state, galectin-9 binding to glycosylated Asn175 of Lamp2 is essential for functionality of lysosomes and autophagy. Loss of N-glycan-binding capability of galectin-9 causes its complete depletion from lysosomes and defective autophagy, leading to increased endoplasmic reticulum (ER) stress preferentially in autophagy-active Paneth cells and acinar cells. Unresolved ER stress consequently causes cell degeneration or apoptosis that associates with colitis and pancreatic disorders in mice. Therefore, lysosomal galectins maintain homeostatic function of lysosomes to prevent organ pathogenesis.

Date: 2020
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DOI: 10.1038/s41467-020-18102-7

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