The CARD11-BCL1-MALT1 complex activates the transcription factor NF-κB downstream of antigen receptor signaling in B cells. In Nature Communications, Overall and colleagues use a highly sensitive proteomics approach (TAILS) in B cells from a patient with homozygous mutation of the gene encoding the paracaspase MALT1 to identify the ubiquitin ligase HOIL1, a component of the linear ubiquitin chain–assembly complex (LUBAC), as a substrate of MALT1 in human lymphocytes. MALT1 cleaves HOIL1, but not other LUBAC subunits, which leads to disengagement of HOIL1 from LUBAC, disassembly of LUBAC, less linear ubiquitination of target proteins, such as RIP1 and NEMO, and less activation of NF-κB. The initial triggering of NF-κB signaling downstream the antigen receptor in B cells and T cells is independent of MALT1's paracaspase activity, which suggess that the scaffolding role of MALT1 is more important at early stages, while cleavage of HOIL1 decreases NF-κB activation at later time points. These studies also show that HOIL1 is a target of MALT1 in mouse lymphocytes as well.

Nat. Comm. (3 November 2015) doi:10.1038/ncomms9777