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Nat Commun. 2015 Nov 3;6:8777. doi: 10.1038/ncomms9777.

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

Author information

1
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
2
Department of Oral Biological and Medical Science, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
3
Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
4
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
5
Child &Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada V6T 1Z3.
6
Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
7
Thermo Fisher Scientific, 355 River Oaks Parkway, San Jose, 95134 California, USA.
8
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
9
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
10
Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.

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.

PMID:
26525107
PMCID:
PMC4659944
DOI:
10.1038/ncomms9777
[Indexed for MEDLINE]
Free PMC Article

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