Role of K63-linked polyubiquitination in NF-κB signalling: which ligase catalyzes and what molecule is targeted?

Nuclear factor-κB (NF-κB) is a master regulator of immunity and also involved in malignant transformation. It has been widely accepted that Lys-48 (K48)-linked polyubiquitination plays a critical role in NF-κB signalling by targeting inhibitor of NF-κB (IκB), thereby leading to its degradation by the proteasome. Alternatively, studies on IL-1 and TNF signalling have revealed that proteins modified with K63-linked polyubiquitin chains do not undergo the proteasomal degradation, instead, function as the signalling platforms required for the activation of the IκB kinase (IKK) complex. From the studies on lymphoid malignancies, human T cell leukaemia virus 1-derived protein, Tax, has been shown to activate the IKK complex, although the mechanism is largely unknown. Recently, Shibata et al. (Activation of the IκB kinase complex by HTLV-1 Tax requires cytosolic factors involved in Tax-induced polyubiquitination. J. Biochem. 150: 679-686, 2011) has established a cell free IKK assay system and demonstrated that recombinant Tax protein can activate the IKK complex in a K63-linked-polyubiquitination-dependent manner. This cell free assay system will be useful for the identification of various key players responsible for Tax-induced IKK activation.