Cargando…
Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation
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 (CR...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291148/ https://www.ncbi.nlm.nih.gov/pubmed/34392531 http://dx.doi.org/10.1002/eji.202149269 |
_version_ | 1784749076719337472 |
---|---|
author | Fionda, Cinzia Stabile, Helena Molfetta, Rosa Kosta, Andrea Peruzzi, Giovanna Ruggeri, Silvia Zingoni, Alessandra Capuano, Cristina Soriani, Alessandra Paolini, Rossella Gismondi, Angela Cippitelli, Marco Santoni, Angela |
author_facet | Fionda, Cinzia Stabile, Helena Molfetta, Rosa Kosta, Andrea Peruzzi, Giovanna Ruggeri, Silvia Zingoni, Alessandra Capuano, Cristina Soriani, Alessandra Paolini, Rossella Gismondi, Angela Cippitelli, Marco Santoni, Angela |
author_sort | Fionda, Cinzia |
collection | PubMed |
description | 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 cell migration. 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. |
format | Online Article Text |
id | pubmed-9291148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92911482022-07-20 Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation Fionda, Cinzia Stabile, Helena Molfetta, Rosa Kosta, Andrea Peruzzi, Giovanna Ruggeri, Silvia Zingoni, Alessandra Capuano, Cristina Soriani, Alessandra Paolini, Rossella Gismondi, Angela Cippitelli, Marco Santoni, Angela Eur J Immunol Molecular immunology and signaling 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 cell migration. 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. John Wiley and Sons Inc. 2021-09-18 2021-11 /pmc/articles/PMC9291148/ /pubmed/34392531 http://dx.doi.org/10.1002/eji.202149269 Text en © 2021 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Molecular immunology and signaling Fionda, Cinzia Stabile, Helena Molfetta, Rosa Kosta, Andrea Peruzzi, Giovanna Ruggeri, Silvia Zingoni, Alessandra Capuano, Cristina Soriani, Alessandra Paolini, Rossella Gismondi, Angela Cippitelli, Marco Santoni, Angela Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation |
title | Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation |
title_full | Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation |
title_fullStr | Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation |
title_full_unstemmed | Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation |
title_short | Cereblon regulates NK cell cytotoxicity and migration via Rac1 activation |
title_sort | cereblon regulates nk cell cytotoxicity and migration via rac1 activation |
topic | Molecular immunology and signaling |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291148/ https://www.ncbi.nlm.nih.gov/pubmed/34392531 http://dx.doi.org/10.1002/eji.202149269 |
work_keys_str_mv | AT fiondacinzia cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT stabilehelena cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT molfettarosa cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT kostaandrea cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT peruzzigiovanna cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT ruggerisilvia cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT zingonialessandra cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT capuanocristina cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT sorianialessandra cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT paolinirossella cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT gismondiangela cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT cippitellimarco cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation AT santoniangela cereblonregulatesnkcellcytotoxicityandmigrationviarac1activation |