Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination.
Mélanie JuillandNagham AloucheIvana UbezziMontserrat GonzalezHarun-Or RashidLeonardo ScarpellinoTabea ErdmannMichael GrauGeorg LenzSanjiv A LutherMargot ThomePublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.
Keyphrases
- cell adhesion
- gene expression
- bone marrow
- induced apoptosis
- endothelial cells
- diffuse large b cell lymphoma
- dna binding
- small cell lung cancer
- signaling pathway
- mesenchymal stem cells
- cell migration
- adipose tissue
- stem cells
- oxidative stress
- pseudomonas aeruginosa
- cystic fibrosis
- staphylococcus aureus
- transcription factor
- small molecule
- tyrosine kinase
- structural basis
- toll like receptor
- protein kinase
- pluripotent stem cells