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

ABSTRACT: MALT1 controls several receptors-mediated signaling to nuclear factor ?B (NF-?B) through both its scaffold and protease function. MALT1 protease activity is shown to inactivate several negative regulators of NF-?B signaling and augment NF-?B 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-?B 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 I?B? phosphorylation activity as MALT1. Truncated MALT1_1-781 mutant showed weakness in I?B? phosphorylation and the expression of NF-?B targets IL-2 and IFN-?. 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.

SUBMITTER: Wu CH 

PROVIDER: S-EPMC6023146 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature