title: The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling.
abstract: Antigen-receptor-mediated activation of lymphocytes relies on a signalosome comprising CARMA1 (also known as CARD11), BCL10 and MALT1 (the CBM complex). The CBM activates nuclear factor κB (NF-κB) transcription factors by recruiting the 'linear ubiquitin assembly complex' (LUBAC), and unleashes MALT1 paracaspase activity. Although MALT1 enzyme shapes NF-κB signaling, lymphocyte activation and contributes to lymphoma growth, the identity of its substrates continues to be elucidated. Here, we report that the LUBAC subunit HOIL1 (also known as RBCK1) is cleaved by MALT1 following antigen receptor engagement. HOIL1 is also constitutively processed in the 'activated B-cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), which exhibits aberrant MALT1 activity. We further show that the overexpression of MALT1-insensitive HOIL1 mitigates T-cell-receptor-mediated NF-κB activation and subsequent cytokine production in lymphocytes. Thus, our results unveil HOIL1 as a negative regulator of lymphocyte activation cleaved by MALT1. This cleavage could therefore constitute an appealing therapeutic target for modulating immune responses.
authors.affiliation: INSERM U892, Cancer Research Center Nantes-Angers, Nantes 44007, France CNRS UMR6299, Cancer Research Center Nantes-Angers, Nantes 44007, France University of Nantes, Nantes 44007, France Team SOAP: 'Signaling in Oncogenesis, Angiogenesis, and Permeability', Cancer Research Center Nantes-Angers, IRS-UN blg, Room 416, 8 quai Moncousu, Nantes 44007, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Douanne
authors.affiliation: INSERM U892, Cancer Research Center Nantes-Angers, Nantes 44007, France CNRS UMR6299, Cancer Research Center Nantes-Angers, Nantes 44007, France University of Nantes, Nantes 44007, France Team SOAP: 'Signaling in Oncogenesis, Angiogenesis, and Permeability', Cancer Research Center Nantes-Angers, IRS-UN blg, Room 416, 8 quai Moncousu, Nantes 44007, France.
authors.forename: Julie
authors.identifier: 0000-0002-7985-9007
authors.initials: J
authors.lastname: Gavard
authors.affiliation: INSERM U892, Cancer Research Center Nantes-Angers, Nantes 44007, France CNRS UMR6299, Cancer Research Center Nantes-Angers, Nantes 44007, France University of Nantes, Nantes 44007, France Team SOAP: 'Signaling in Oncogenesis, Angiogenesis, and Permeability', Cancer Research Center Nantes-Angers, IRS-UN blg, Room 416, 8 quai Moncousu, Nantes 44007, France nicolas.bidere@inserm.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bidère
mesh_terms: D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
keywords: LUBAC; Lymphocyte; Lymphoma; MALT1; NF-κB; Signaling