A Rasa3-Gαi signaling axis orchestrates B lymphocyte trafficking into and through lymphoid organs

By modulating integrin affinity, the GTP/GDP status of Rap1 affects the arrest, transendothelial migration, and the trafficking of lymphocytes, yet how chemoattractant receptors control Rap1 remains incompletely resolved. Rasa3, a Rap1 GTPase-activating protein, limits the duration that Rap1 remains GTP bound. Here, we investigated how Rasa3 deficiency impacted chemoattractant receptor signaling and B lymphocyte trafficking in mice. The loss of Rasa3 disrupted the usual dynamic regulation of the GDP/GTP status of Rap1 causing a striking phenotype characterized by a severe maldistribution of B cells within lymphoid organs and major reductions in mucosal and blood B cells. Rasa3 loss raised basal Rap1-GTP levels, disrupted integrin binding, and unexpectedly caused defects in chemoattractant receptor signaling. At the plasma membrane GTP-bound but not GDP-bound Gαi resided within 10 angstroms of Rasa3. Thus, Rasa3 couples Gαi signaling to Rap1-GTP levels tuning chemokine signaling and integrin affinity to promote B lymphocyte trafficking and function.