HTLV-1 Tax Induces Formation of the Active Macromolecular IKK Complex by Generating Lys63- and Met1-Linked Hybrid Polyubiquitin Chains

• DOI: 10.1371/journal.ppat.1006162
• Publication Date: 2017-01-19T20:13:46Z
• Authors: Yuri Shibata; Fuminori Tokunaga; Eiji Goto; Ginga Komatsu; Jin Gohda; Yasushi Saeki; Keiji Tanaka; Hirotaka Takahashi; Tatsuya Sawasaki; Satoshi Inoue; Hiroyuki Oshiumi; Tsukasa Seya; Hiroyasu Nakano; Yuetsu Tanaka; Kazuhiro Iwai; Jun-ichiro Inoue
• Keywords: IκB kinase

The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is crucial for the development adult (ATL), a highly malignant CD4+ T cell neoplasm. Among multiple aberrant Tax-induced effects on cellular processes, persistent activation transcription factor NF-κB, which activated only transiently upon physiological stimulation, essential leukemogenesis. We and others have shown that induces IκB kinase (IKK) complex, critical step in NF-κB activation, by generating Lys63-linked polyubiquitin chains. However, molecular mechanism underlying IKK controversial not fully understood. Here, we demonstrate recruits linear (Met1-linked) ubiquitin chain assembly complex (LUBAC) to fails induce cells lack LUBAC activity. Mass spectrometric analyses revealed both Met1-linked chains are associated with complex. Furthermore, treatment IKK-associated Met1-linked-chain-specific deubiquitinase (OTULIN) resulted reduction high weight generation short chains, indicating can Lys63- hybrid also formation active macromolecular blocking synthesis inhibited Taken together, these results lead us propose novel model hybrid-chain-dependent oligomerization triggered leads trans-autophosphorylation-mediated activation.