Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB).
Azpilikueta A., Bolaños E., Lang V., Labiano S., Aznar MA., Etxeberria I., Teijeira A., Rodriguez-Ruiz ME., Perez-Gracia JL., Jure-Kunkel M., Zapata JM., Rodriguez MS., Melero I.
TRAF2 dependent K63-polyubiquitinations have been recently shown to connect CD137 (4-1BB) stimulation to NF-κB activation. In a search of deubiquitinase enzymes (DUBs) that could regulate such a signaling route, A20 and CYLD were found to coimmunoprecipitate with CD137 and TRAF2 complexes. Indeed, overexpression of A20 or CYLD downregulated CD137-elicited ubiquitination of TRAF2 and TAK1 upon stimulation with agonist monoclonal antibodies. Moreover, overexpression of A20 or CYLD downregulated CD137-induced NF-κB activation in cultured cells and in gene-transferred hepatocytes in vivo, while silencing these deubiquitinases enhanced CD137 costimulation of primary human CD8 T cells. Therefore A20 and CYLD directly downregulate the signaling from a T and NK-cell costimulatory receptor under exploitation for cancer immunotherapy in clinical trials.