HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains

PLoS Pathogens

Wenying Long¹  Chong Wang¹  Ailing Wu¹  Qiong Zhang¹  Xiaotao Duan¹  Xiaoqing Zhang¹  Yuetsu Tanaka²  Chao Peng²  Lin Hu³  Zongping Xia³  Catherine C. L. Wong⁴ 

[1] Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China;National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China;State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China

关键词: Transcription factors;    Ubiquitination;    293T cells;    HTLV-1;    T cells;    Immunoblotting;    Phosphorylation;    Ubiquitin ligases;   

DOI  :  10.1371/journal.ppat.1005584

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.

【 授权许可】

CC BY