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

Author

Listed:
  • Zilin Nie

    (University of Michigan Medical School)

  • Ming-Qing Du

    (University of Cambridge)

  • Linda M. McAllister-Lucas

    (University of Pittsburgh School of Medicine)

  • Peter C. Lucas

    (University of Pittsburgh School of Medicine)

  • Nathanael G. Bailey

    (University of Michigan Medical School)

  • Cory M. Hogaboam

    (University of Michigan Medical School)

  • Megan S. Lim

    (University of Michigan Medical School
    Center for Computational Medicine and Bioinformatics, University of Michigan Medical School)

  • Kojo S. J. Elenitoba-Johnson

    (University of Michigan Medical School
    Center for Computational Medicine and Bioinformatics, University of Michigan Medical School
    Protein Folding Diseases Initiative, University of Michigan Medical School)

Abstract

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.

Suggested Citation

  • Zilin Nie & Ming-Qing Du & Linda M. McAllister-Lucas & Peter C. Lucas & Nathanael G. Bailey & Cory M. Hogaboam & Megan S. Lim & Kojo S. J. Elenitoba-Johnson, 2015. "Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms6908
    DOI: 10.1038/ncomms6908
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