ARF6 Interacts with JIP4 to Control a Motor Switch Mechanism Regulating Endosome Traffic in Cytokinesis

Background: Recent work has highlighted the importance of the recycling of endocytic membranes to the intercellular bridge for completion of cytokinesis in animal cells. ADP-ribosylation factor 6 (ARF6), which localizes to the plasma membrane and endosomal compartments, regulates endocytic recycling to the bridge during cytokinesis and is required for abscission. Results: Here, we report that the JNK-interacting proteins JIP3 and JIP4, two highly related scaffolding proteins for JNK signaling modules, also acting as binding partners of kinesin-1 and dynactin complex, can function as downstream effectors of ARF6. In vitro, binding of GTP-ARF6 to the second leucine zipper domain of JIP3 and JIP4 interferes with JIPs' association with kinesin-1, whereas it favors JIPs' interaction with the dynactin complex. With protein silencing by small interfering RNA and dominant inhibition approaches, we show that ARF6, JIP4, kinesin-1, and the dynactin complex control the trafficking of recycling endosomes in and out of the intercellular bridge and are necessary for abscission. Conclusion: Our findings reveal a novel function for ARF6 as a regulatory switch for motor proteins of opposing direction that controls trafficking of endocytic vesicles within the intercellular bridge in a mechanism required for abscission.