Autocleavage of the paracaspase MALT1 at Arg-781 attenuates NF-κB signaling and regulates the growth of activated B-cell like diffuse large B-cell lymphoma cells

• Published in: PloS one 2018-06, Vol.13 (6), p.e0199779-e0199779
• Main Authors: Wu, Chun-Hsien, Yang, Yu-Hsuan, Chen, Mei-Ru, Tsai, Ching-Hwa, Cheng, Ann-Lii, Doong, Shin-Lian
• Format: Article
• Language: English
• Subjects: Arginine; B-cell lymphoma; Bcl-10 protein; Biology and Life Sciences; Biotechnology; C-Terminus; Cancer; CD3 antigen; Cell activation; Cell survival; Cleavage; Gene expression; Interleukin 2; Ionomycin; Kinases; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Medicine; Medicine and Health Sciences; NF-κB protein; Oligomerization; Paracaspases; Penicillin; Phosphorylation; Protease; Proteinase; Proteins; Proteolysis; Receptors; Regulators; Research and Analysis Methods; Signaling; TRAF6 protein; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0199779

MALT1 controls several receptors-mediated signaling to nuclear factor κB (NF-κB) through both its scaffold and protease function. MALT1 protease activity is shown to inactivate several negative regulators of NF-κB signaling and augment NF-κB activation ability. In this study, MALT1 was demonstrated to autoprocess itself in the presence of oligomerization-competent BCL10. Cleavage occurred after Arginine 781 located in the C-terminus of MALT1. Shortened MALT1 cleavage products showed attenuated binding ability with TRAF6. Its NF-κB activation ability was also weakened. Various MALT1 constructs including wild type, catalytically-inactive (MALT1_C464A), cleavage-defective (MALT1_R781L), or truncated (MALT1_1-781) form of MALT1 was introduced into MALT1-knocked-down-Jurkat T cells. Cleavage-defective MALT1_R781L retained its proteolytic and initial IκBα phosphorylation activity as MALT1. Truncated MALT1_1-781 mutant showed weakness in IκBα phosphorylation and the expression of NF-κB targets IL-2 and IFN-γ. Cleavage at R781 was detectable but marginal after activation with TPA/ionomycin or anti-CD3 antibody in lymphocytes. However, cleavage at R781 was evident in ABC-DLBCL cells such as OCI-Ly3, HBL-1. HBL-1 cells with induced expression of catalytically-inactive MALT1_C464A or cleavage-defective MALT1_R781L exhibited characteristic of retarded-growth. These findings suggested that cleavage at R781 of MALT1 played a role in the survival of ABC-DLBCL cells.