Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma

• Published in: Nature communications 2015-01, Vol.6 (1), p.5908-5908, Article 5908
• Main Authors: Nie, Zilin, Du, Ming-Qing, McAllister-Lucas, Linda M., Lucas, Peter C., Bailey, Nathanael G., Hogaboam, Cory M., Lim, Megan S., Elenitoba-Johnson, Kojo S. J.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/31; 14; 14/35; 42/89; 631/337; 631/45/612/1243; 692/699/1541/1990/291/1621/1915; 82/1; 82/58; 96/44; 96/63; Antibiotics; Antigens; Apoptosis; Carcinogenesis - metabolism; Cytoskeletal Proteins - metabolism; Drug resistance; HEK293 Cells; Humanities and Social Sciences; Humans; Lymphoma; Lymphoma, B-Cell, Marginal Zone - metabolism; Lymphoma, B-Cell, Marginal Zone - physiopathology; Mass Spectrometry; Microscopy, Fluorescence; multidisciplinary; Mutagenesis, Site-Directed; Oncogene Proteins, Fusion - metabolism; Pathogenesis; Pathology; Plasmids - genetics; Proteins; Proteolysis; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Scientific imaging; Tumor Stem Cell Assay; Tumor Suppressor Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6908

MALT1 is the only known paracaspase and is a critical mediator of B- and T-cell receptor signalling. The function of the MALT1 gene is subverted by oncogenic chimeric fusions arising from the recurrent t(11;18)(q21;q21) aberration, which is the most frequent translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. API2–MALT1 -positive MALT lymphomas manifest antibiotic resistance and aggressive clinical behaviour with poor clinical outcome. However, the mechanisms underlying API2–MALT1 -induced MALT lymphomagenesis are not fully understood. Here we show that API2–MALT1 induces paracaspase-mediated cleavage of the tumour suppressor protein LIMA1. LIMA1 binding by API2–MALT1 is API2 dependent and proteolytic cleavage is dependent on MALT1 paracaspase activity. Intriguingly, API2–MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo . Importantly, primary MALT lymphomas harbouring the API2–MALT1 fusion uniquely demonstrate LIMA1 cleavage fragments. Our studies reveal a novel paracaspase-mediated oncogenic gain-of-function mechanism in the pathogenesis of MALT lymphoma. Protein fusions between the paracaspase MALT1 and API2 (inhibitor of apoptosis 2) are found in B-cell lymphoma. Here the authors identify the tumour suppressor LIMA1 as a new target of API2–MALT1 chimeric protein and show that API2–MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo .