The WNK-OXSR1 Osmosensing Pathway Mediates Intestinal Regeneration Through Hippo-YAP Signaling

ABSTRACT: Abstract Animals activate regenerative processes to repair injuries and restore homeostasis following tissue damage. A central question in regeneration is how damage signals are sensed and translated into regenerative growth. Tissue injuries lead to the release of intracellular contents and bodily fluids and disturb osmotic balance. However, the role of osmolarity in regeneration remains largely unexplored. Using Drosophila and mouse intestine, and samples from inflammatory bowel disease (IBD) patients, we identify a key role for the osmolarity-sensing WNK-OXSR1 signaling pathway in intestinal regeneration. Mechanistically, upon intestinal injury, OXSR1 phosphorylates the RhoB GTPase at threonine 37, disrupting its interaction with ARHGAP17, increasing GTP-bound RhoB, enhancing F-actin polymerization, and activating YAP to drive regeneration. We further show that pharmacologically inhibiting WNK or OXSR1 reduces the oncogenic potential of intestinal regeneration. These findings reveal osmolarity as a critical damage signal in regeneration and position WNK-OXSR1 as a potential therapeutic target to promote intestinal repair.

ORGANISM(S): Homo sapiens (human) Mus musculus (mouse) Drosophila melanogaster (fruit fly)

SUBMITTER: Xiawei Huang 

PROVIDER: S-BSST2346 | biostudies-other |

REPOSITORIES: biostudies-other