Stabilization of the TAK1 adaptor proteins TAB2 and TAB3 is critical for optimal NF-κB activation.

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 (IKKα/IKKβ/IKKγ) complex, which is recruited to M1-linked polyubiquitin chains via the IKKγ (NEMO) component. Together, the two complexes activate the NF-κB family of transcription factors. NF-κB 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 stability by the deubiquitinase USP15. Comment on: https://doi.org/10.1111/febs.15202.