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

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 lympho...

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Bibliographic Details
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:
Antibiotics
Antigens
Apoptosis
Carcinogenesis - metabolism
Cytoskeletal Proteins - metabolism
Drug resistance
HEK293 Cells
Humans
Lymphoma
Lymphoma, B-Cell, Marginal Zone - metabolism
Lymphoma, B-Cell, Marginal Zone - physiopathology
Mass Spectrometry
Microscopy, Fluorescence
Mutagenesis, Site-Directed
Oncogene Proteins, Fusion - metabolism
Pathogenesis
Pathology
Plasmids - genetics
Proteins
Proteolysis
RNA, Small Interfering - genetics
Scientific imaging
Tumor Stem Cell Assay
Tumor Suppressor Proteins - metabolism
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms6908