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Klein T.,University of British Columbia | Fung S.-Y.,University of British Columbia | Fung S.-Y.,Child AndFamily Research Institute | Renner F.,Novartis | And 17 more authors.
Nature Communications | Year: 2015

Antigen receptor signalling activates the canonical NF-κ B 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-κ B 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-κ B activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-κ B activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-κ B pathway - first promoting activation via the CBM - then triggering HOIL1-dependent negative-feedback termination, preventing reactivation. © 2015 Macmillan Publishers Limited. All rights reserved. Source

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