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The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling.

Klein, Theo and Fung, Shane-Yu and Renner, Florian and Blank, Michael and Dufour, Antoine and Kang , Sohyeong and Bolger-Munro, Madison and Scurll, Joshua and Priatel, John and Schweigler, Patrick and Melkko, Samu and Gold, Michael and Viner, Rosa and Regnier, Catherine and Turvey, Stuart and Overall, Christopher (2015) The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling. Nature Communications, 6. p. 8777. ISSN 2041-1723

Abstract

Antigen receptor signalling activates the canonical NF-κB pathway via the CARD11/BCL10/MALT1 (CBM) signalosome involving key, yet ill-defined roles for linear ubiquitination. The paracaspase MALT1 cleaves and removes negative checkpoint proteins, amplifying lymphocyte responses in NF-κB activation and in B-cell lymphoma subtypes. To identify new human MALT1 substrates, we compare B cells from the only known living MALT1(mut/mut) patient with healthy MALT1(+/mut) family members using 10-plex Tandem Mass Tag TAILS N-terminal peptide proteomics. We identify HOIL1 of the linear ubiquitin chain assembly complex as a novel MALT1 substrate. We show linear ubiquitination at B-cell receptor microclusters and signalosomes. Late in the NF-κB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-κB activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-κB pathway-first promoting activation via the CBM--then triggering HOIL1-dependent negative-feedback termination, preventing reactivation.

Item Type: Article
Keywords: MALT1
Date Deposited: 23 May 2016 23:45
Last Modified: 23 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/24428

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