Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (52), p.e2301155120
Main Authors: Juilland, Mélanie, Alouche, Nagham, Ubezzi, Ivana, Gonzalez, Montserrat, Rashid, Harun-Or, Scarpellino, Leonardo, Erdmann, Tabea, Grau, Michael, Lenz, Georg, Luther, Sanjiv A, Thome, Margot
Format: Article
Language:English
Subjects:
Adhesion
Adult
Animals
B-cell lymphoma
Biological Sciences
Bone marrow
Caspases - metabolism
Cell activation
Cell adhesion
Cell adhesion & migration
Cell Adhesion - genetics
Cleavage
Gene expression
Humans
In vivo methods and tests
Integrins
Kinases
Lymphocytes
Lymphocytes B
Lymphocytes T
Lymphoma
Lymphoma, Large B-Cell, Diffuse - genetics
Metastases
Mice
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - genetics
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - metabolism
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
NF-kappa B - metabolism
Substrates
Tensin
Tensins - genetics
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Summary: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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2301155120