TAK1 ubiquitination regulates doxorubicin-induced NF-κB activation

► TAK1 is required for doxorubicin (Dox)-induced NF-κB activation. ► Lys63-linked TAK1 polyubiquitination at lysine 158 residue is required for Dox-induced NF-κB activation. ► USP4 inhibits Dox-induced Lys63-linked TAK1 polyubiquitination and NF-κB activation. ► Dox induces Lys48-linked TAK1 polyubiquitination to promote TAK1 degradation. ► ITCH inhibits Dox-induced NF-κB activation by promoting Lys48-linked TAK1 polyubiquitination and its subsequent degradation.