Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation

Rearrangement of the actin cytoskeleton is critical for cytotoxic and immunoregulatoryfunctions as well as migration of natural killer (NK) cells. However, dynamic reorganizationof actin is a complex process, which remains largely unknown. Here, we investigatedthe role of the protein Cereblon (CRBN), an E3 ubiquitin ligase complex co-receptor andthe primary target of the immunomodulatory drugs, in NK cells.We observed that CRBNpartially colocalizes with F-actin in chemokine-treated NK cells and is recruited to theimmunological synapse, thus suggesting a role for this protein in cytoskeleton reorganization.Accordingly, silencing of CRBN in NK cells results in a reduced cytotoxicity that correlateswith a defect in conjugate and lytic synapse formation. Moreover, CRBN depletionsignificantly impairs the ability of NK cells to migrate and reduces the enhancing effect oflenalidomide on NK cellmigration. Finally,we provided evidence that CRBN is required foractivation of the small GTPase Rac1, a critical mediator of cytoskeleton dynamics. Indeed,in CRBN-depleted NK cells, chemokine-mediated or target cell–mediated Rac1 activationis significantly reduced. Altogether our data identify a critical role for CRBN in regulatingNK cell functions and suggest that this protein may mediate the stimulatory effect oflenalidomide on NK cells.