Malt1-dependent cleavage of Tensin-3 controls B-cell adhesion and lymphomagenesis

Abstract

AbstractThe protease Malt1 controls the development and function of lymphocytes and promotes lymphomagenesis by cleaving a limited set of cellular substrates, many of which regulate gene transcription. Here, we report the identification of the integrin-binding scaffold protein Tensin-3 as a Malt1 substrate in activated B cells. B cells expressing a non-cleavable form of Tensin-3 (TNS3-nc) showed normal NF-κB and JNK transcriptional responses but increased and prolonged integrin-dependent adhesion upon activation. Moreover, mice expressing a non-cleavable form of Tensin-3 displayed reduced antibody production in response to immunization with a T-cell dependent antigen. We also explored the role of Tensin-3 in diffuse large B cell lymphomas and mantle cell lymphomas characterized by constitutive Malt1 activity, which showed strong constitutive Tensin-3 cleavage and a correlating reduction in total Tensin-3 levels. Silencing of Tensin-3 expression in Malt1-driven lymphoma models did not affect cellular proliferation but enhanced the dissemination of xenografted lymphoma cells. Thus, Malt1-dependent Tensin-3 cleavage limits integrin-dependent B-cell adhesion and promotes humoral immune responses and metastatic spreading of B cell lymphomas in a transcription-independent manner.