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

Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation / Fionda, Cinzia; Stabile, Maria Helena; Molfetta, Rosa; Kosta, Andrea; Peruzzi, Giovanna; Ruggeri, Silvia; Zingoni, Alessandra; Capuano, Cristina; Soriani, Alessandra; Paolini, Rossella; Gismondi, Angela; Cippitelli, Marco; Santoni, Angela. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 1521-4141. - (2021). [10.1002/eji.202149269]

Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation

Cinzia Fionda
;
Helena Stabile
Co-primo
;
Rosa Molfetta;Andrea Kosta;Giovanna Peruzzi;Silvia Ruggeri;Alessandra Zingoni;Cristina Capuano;Alessandra Soriani;Rossella Paolini;Angela Gismondi;Marco Cippitelli;Angela Santoni
2021

Abstract

Rearrangement of the actin cytoskeleton is critical for cytotoxic and immunoregulatory functions as well as migration of natural killer (NK) cells. However, dynamic reorganization of actin is a complex process, which remains largely unknown. Here, we investigated the role of the protein Cereblon (CRBN), an E3 ubiquitin ligase complex co-receptor and the primary target of the immunomodulatory drugs, in NK cells.We observed that CRBN partially colocalizes with F-actin in chemokine-treated NK cells and is recruited to the immunological synapse, thus suggesting a role for this protein in cytoskeleton reorganization. Accordingly, silencing of CRBN in NK cells results in a reduced cytotoxicity that correlates with a defect in conjugate and lytic synapse formation. Moreover, CRBN depletion significantly impairs the ability of NK cells to migrate and reduces the enhancing effect of lenalidomide on NK cellmigration. Finally,we provided evidence that CRBN is required for activation of the small GTPase Rac1, a critical mediator of cytoskeleton dynamics. Indeed, in CRBN-depleted NK cells, chemokine-mediated or target cell–mediated Rac1 activation is significantly reduced. Altogether our data identify a critical role for CRBN in regulating NK cell functions and suggest that this protein may mediate the stimulatory effect of lenalidomide on NK cells.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1569443
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