The ubiquitin C‐terminal hydrolase UCH‐L1 regulates B‐cell proliferation and integrin activation

The ubiquitin C‐terminal hydrolase‐L1 (UCH‐L1) is a deubiquitinating enzyme that catalyses the hydrolysis of polyubiquitin precursors and small ubiquitin adducts. UCH‐L1 has been detected in a variety of malignant and metastatic tumours but its biological function in these cells is unknown. We have previously shown that UCH‐L1 is highly expressed in Burkitt’s lymphoma (BL) and is up‐regulated upon infection of B lymphocytes with Epstein–Barr virus (EBV). Here we show that knockdown of UCH‐L1 by RNAi inhibits the proliferation of BL cells in suspension and semisolid agar and activates strong LFA‐1‐dependent homotypic adhesion. Induction of cell adhesion correlated with cation‐induced binding to ICAM‐1, clustering of LFA‐1 into lipid rafts and constitutive activation of the Rap1 and Rac1 GTPases. Expression of a catalytically active UCH‐L1 promoted the proliferation of a UCH‐L1‐negative EBV transformed lymphoblastoid cell line (LCL) and inhibited cell adhesion, whereas a catalytic mutant had no effect, confirming the requirement of UCH‐L1 enzymatic activity for the regulation of these phenotypes. Our results identify UCH‐L1 as a new player in the signalling pathways that promote the proliferation and invasive capacity of malignant B cells.