Klein, Theo, Fung, Shane-Yu, Renner, Florian, Blank, Michael, Dufour, Antoine, Kang , Sohyeong, Bolger-Munro, Madison, Scurll, Joshua, Priatel, John, Schweigler, Patrick, Melkko, Samu, Gold, Michael, Viner, Rosa, Regnier, Catherine, 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