title: The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling.
abstract: The API2-MALT1 fusion oncoprotein is created by the recurrent t(11;18)(q21;q21) chromosomal translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. We identified receptor interacting protein-1 (RIP1) as a novel API2-MALT1-associated protein, and demonstrate that RIP1 is required for API2-MALT1 to stimulate canonical nuclear factor kappa B (NF-κB). API2-MALT1 promotes ubiquitination of RIP1 at lysine (K) 377, which is necessary for full NF-κB activation. Furthermore, we found that TNF receptor-associated factor 2 (TRAF2) recruitment is required for API2-MALT1 to induce RIP1 ubiquitination, NF-κB activation and cellular transformation. Although both TRAF2 and RIP1 interact with the API2 moiety of API2-MALT1, this moiety alone is insufficient to induce RIP1 ubiquitination or activate NF-κB, indicating that API2-MALT1-dependent RIP1 ubiquitination represents a gain of function requiring the concerted actions of both the API2 and MALT1 moieties of the fusion. Intriguingly, constitutive RIP1 ubiquitination was recently demonstrated in several solid tumors, and now our study implicates RIP1 ubiquitination as a critical component of API2-MALT1-dependent lymphomagenesis.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rosebeck
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: A O
authors.initials: AO
authors.lastname: Rehman
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: I J
authors.initials: IJ
authors.lastname: Apel
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kohrt
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Laboratory Block, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Appert
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: O'Donnell
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Ting
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Laboratory Block, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: M-Q
authors.initials: MQ
authors.lastname: Du
authors.affiliation: 1] Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, Catholic University Leuven, Leuven, Belgium [2] Human Genome Laboratory, Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Baens
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Lucas
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: McAllister-Lucas
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D009857:Oncogenes; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination
chemical_list: C119724:AGFG1 protein, human; C415943:API2-MALT1 fusion protein, human; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D016601:RNA-Binding Proteins; D047992:TNF Receptor-Associated Factor 2