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

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 Asn 175 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.

Multi-omics of the esophageal microenvironment identifies signatures associated with progression of Barrett’s esophagus

“…Knock-out of LprI_01601 did lead to decreased intracellular survival, and this finding was validated with the C. rectus LprI_00928 mutant, but the mechanism appeared to be independent of lysozyme. Indeed, on preliminary screen, recombinant LprI_01601 did not appear to interact with human lysozyme but was pulled down along with the lysosomal cysteine protease cathepsin S, galectin 9 [ 69 ], and legumain, of which the former is a substrate [ 70 ]. Notably, cathepsin S and galectin 9 were upregulated in patients with MET in our cohort.…”

The Role of Autophagy in Skeletal Muscle Diseases

“…A recent study has demonstrated that the Asn175 site at the linker region between N- and C-terminal subdomains of LAMP2 is critical for its role in autophagy. Loss of glycosylation at the Asn175 disrupts the interaction between Lamp2 and galectin-9 protein, which impairs endolysosome/lysosome function and cargo degradation ( Sudhakar et al, 2020 ).…”

Placental Glycoredox Dysregulation Associated with Disease Progression in an Animal Model of Superimposed Preeclampsia

“…Similar results have been observed in vivo by using a placenta-specific Atg7 (essential for autophagy) conditional knockout mouse model [ 68 ], which results in autophagy deficiency accompanied by poor placentation and elevated maternal blood pressure, suggesting its correlation with the pathophysiology of PE. Notably, both Gal-3 and Gal-9 have been implicated in the control of autophagy, acting as negative (Gal-3 [ 69 ]) and positive (Gal-9, mediated by polyLacNAc recognition [ 70 , 71 ]) modulators, respectively. These findings are in agreement with our observation that SHRSP implantations exhibited decreased Gal-9 and upregulated Gal-3 levels already at the onset of the disease and reduced polyLacNAc presentation (LEA staining) in placental compartments, which would possibly lead to impaired autophagy und thus cellular stress.…”

“…These findings are in agreement with our observation that SHRSP implantations exhibited decreased Gal-9 and upregulated Gal-3 levels already at the onset of the disease and reduced polyLacNAc presentation (LEA staining) in placental compartments, which would possibly lead to impaired autophagy und thus cellular stress. Moreover, Sudhakar et al showed that compromised autophagy due to loss of Gal-9 in mouse pancreatic and intestinal cells contributes to increased susceptibility to disease pathogenesis [ 71 ]. These findings led to the assumption that highly secretory cells (i.e., placental cells) are protected from endoplasmic reticulum stress and apoptosis via Gal-9-mediated autophagy that would otherwise lead to tissue inflammation or injury.…”