COMMENTARY Stabilization of the TAK1 adaptor proteins TAB2 and TAB3 is critical for optimal NF-jB activation Harald Braun 1,2 and Jens Staal 1,2,3 1 Department of Biomedical Molecular Biology, Ghent University, Belgium 2 Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium 3 Department of Biochemistry and Microbiology, Ghent University, Belgium Keywords epitransduction; inflammation; lysosome; proteasome; signalophagy Correspondence J. Staal, Department of Biomedical Molecular Biology, VIB center for inflammation research, Ghent University, Technologiepark-Zwijnaarde 71, 9052 Ghent, Belgium Tel: +32-9-3313765 E-mail: jens.staal@irc.vib-ugent.be (Received 30 December 2019, accepted 9 January 2020) doi:10.1111/febs.15210 TAB2 and TAB3 bind to K63-linked polyubiquitin chains and recruit the critical kinase MAP3K7 (TAK1). The polyubiquitin-recruited TAK1/ TAB2/TAB3 complex comes in close proximity with the IKK (IKKa/ IKKb/IKKc) complex, which is recruited to M1-linked polyubiquitin chains via the IKKc (NEMO) component. Together, the two complexes activate the NF-jB family of transcription factors. NF-jB transcription factors are critical mediators of pro-inflammatory signals and must be tightly regulated at multiple levels. Recently, it was discovered that one such point of regulation occurs at the level of TAB2 and TAB3 protein sta- bility by the deubiquitinase USP15. Comment on: https://doi.org/10.1111/febs.15202 Regulation of signal transduction by post-translational modifications Signal transduction is a complex web of induced pro- tein–protein interactions following post-translational modifications which, among several others, include acetylation, phosphorylation, ubiquitination, and ubiq- uitin-like protein modifications [1]. A prominent subset of this ‘epitransduction code’ is the ‘ubiquitin code’ with polyubiquitin chains that can be assembled on a target protein lysine by several different linkages (M1, K6, K11, K27, K29, K33, K48, K63) [2]. The ubiqui- tin linkage type determines the binding specificity for different polyubiquitin-binding domains and hence dif- ferent interaction partners and functional outcome of the polyubiquitin modification. The ubiquitin code potentially shows even greater structural complexity by the presence of mixed-linkage polyubiquitin chains [2]. In addition to lysine, ubiquitin can also be attached to serine, threonine, and cysteine residues, but very little is known about these modifications [3]. Critical TAK1 ubiquitin adaptor proteins are regulated by degradation Zhou et al. [4] in the current issue nicely show that a deubiquitinase (USP15) is important for optimal NF- jB activation after IL-1b or TNF stimulation. NF-jB activation is highly regulated at several levels since this family of transcription factors are potent inducers of several pro-inflammatory transcripts, and excessive inflammation has been linked to a wide range of dis- eases [5]. Deubiquitination is often discussed in terms Abbreviations K48, lysine 48 (polyubiquitin linkage); K63, lysine 63 (polyubiquitin linkage); KO, knock-out; M1, methionine 1 (polyubiquitin linkage); MAP, mitogen-activated protein; MAP3K, MAP kinase kinase kinase; TAK1, TGF-b-activated kinase 1; USP15, ubiquitin-specific protease 15. 1 The FEBS Journal (2020) ª 2020 Federation of European Biochemical Societies