Simplified model of the role of MALT1 and regnase-1 in B-cell lymphoma. BCR signaling through BTK mediates the formation of a complex of CARD11, BCL10, and MALT1. Oligomerized MALT1, but also the oncoprotein API2-MALT1, functions as a scaffold protein, binding the E3 ubiquitin ligase TRAF6. In parallel, Toll-like receptor (TLR) signaling may result in MyD88-dependent recruitment of IRAK4 and IRAK1, which can also associate with TRAF6. TRAF6 promotes Lys-63–linked ubiquitination of TRAF6 itself as well as TAK1 and IKK-γ/NEMO, resulting in their interaction and TAK1-mediated activation of IKK. IKK mediates phosphorylation and degradation of IκBα, allowing nuclear translocation of NF-κB dimers. In addition, MALT1 (and API2-MALT1) is a protease that cleaves various negative regulators of NF-κB, such as A20, CYLD, and RelB. The deubiquitinating enzymes A20 and CYLD hydrolyze Lys-63–linked polyubiquitin chains of TRAF6, TAK1, and/or NEMO/IKK-γ, whereas RelB can interact with and repress activity of canonical NF-κB subunits; hence, MALT1-dependent inactivation of A20, CYLD, and RelB promotes NF-κB activation and cell growth. The study by Wimberger et al shows that MALT1 protease activity can also regulate gene expression independent of TRAF6/NF-κB, at the posttranscriptional level, by inactivation of the RNA-binding proteins regnase-1 and roquin-1/2, thereby promoting the stability of the NFKBIZ (IκBζ), NFKBID (IκBNS), and ZC3H12A (regnase-1) transcripts. Similar findings are presented for the API2-MALT1 oncoprotein. Professional illustration by Somersault18:24.