WNT2B impairs endosomal trafficking via WASHC5 to inhibit autophagy: a novel non-secretory WNT pathway - PubMed
5 hours ago
- #Crohn's disease
- #non-secretory WNT pathway
- #autophagy inhibition
- WNT2B, typically a secreted ligand, has a non-secretory intracellular function that impairs endosomal trafficking and inhibits autophagy.
- The intracellular WNT2B binds to WASHC5 via its middle domain, disrupting WASH complex assembly and inhibiting actin polymerization on early endosomes.
- This disruption leads to impaired trafficking of ATG9A and other endosomal cargo, resulting in defective autophagy initiation and accumulation of pro-inflammatory and pro-fibrotic factors.
- In a mouse model of chronic colitis, fibroblast-specific deletion of wnt2b restored autophagy, reduced inflammation, and ameliorated intestinal fibrosis.
- In Crohn's disease patients, elevated WNT2B in fibrotic regions correlates negatively with autophagy activity and positively with disease severity and pro-fibrotic phenotypes.
- A novel LC3B-II-dependent autophagic secretion pathway for WNT2B was identified, distinct from conventional ER-to-Golgi secretion.
- The study proposes the WNT2B-WASH complex-ATG9A axis as a regulatory mechanism linking impaired endosomal trafficking to autophagy disruption, inflammation, and fibrosis, suggesting WNT2B as a therapeutic target.