RABEP1 regulates neutrophil migration via endosomal recycling and actin polymerization.
Publication Year:
2026
PubMed ID:
41701563
Funding Grants:
Public Summary:
White blood cells act as the body’s speedy first responders, constantly rushing to the site of an infection to protect us from illness. However, scientists are still trying to understand the exact internal machinery that allows these microscopic defenders to move so effectively. By studying both zebrafish and human cells, researchers recently discovered that a specific protein is absolutely essential for these immune cells to travel. When scientists removed this protein, the cells still knew exactly which direction the infection was coming from, but they completely lost the physical ability to crawl toward it. It turns out that this crucial protein acts like an internal recycling center, constantly breaking down and rebuilding the cell's structural skeleton so it can continuously push itself forward. Ultimately, this discovery provides a vital new piece of the puzzle regarding how our immune system navigates the body, which could eventually help scientists find better ways to boost our natural defenses when we get sick.
Scientific Abstract:
Neutrophils are the first responders of our innate immune system, crucial for defense against various infections. The intricate regulation of neutrophil migration is essential for neutrophil function. However, a complete mechanistic understanding is missing. We previously performed a miRNA overexpression screen and identified miR-190 as a potent suppressor of neutrophil migration in zebrafish. Through a second round of small-scale screening using neutrophil-specific knockouts of putative miR-190 targets, we identified that rabep1 (encoding Rabaptin, RAB GTPase binding effector protein 1) is essential for neutrophil motility and chemotaxis in zebrafish. Re-expressing full-length Rabaptin, but not its truncation lacking the Rab4/Rab5 binding domain, rescued cell motility in the knockout. Knocking down RABEP1 in differentiated human leukemia (dHL-60) cells consistently reduced cell motility. RABAPTIN-deficient dHL-60 cells are defective with fast recycling, yet maintain a normal Rab5 GTP level. The RABAPTIN-deficient cells displayed reduced PAK phosphorylation and decreased F-actin levels, yet still appropriately polarized upon chemokine stimulation. Overexpression of dominant-negative Rab4 or Rab5 has a similar inhibitory effect on neutrophil migration. Our data suggest that RABAPTIN drives endosomal recycling, Rac activation, and leading-edge actin polymerization, providing significant insights into the role of the endocytic pathway in neutrophil motility.