title: Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma.
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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Zilin
authors.initials: Z
authors.lastname: Nie
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Du
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: McAllister-Lucas
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Nathanael G
authors.initials: NG
authors.lastname: Bailey
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.affiliation: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Protein Folding Diseases Initiative, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
mesh_terms: D063646:Carcinogenesis / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000378:metabolism / Q000503:physiopathology*; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C415943:API2-MALT1 fusion protein, human; D003598:Cytoskeletal Proteins; C403263:LIMA1 protein, human; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins