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TAK1 is a ubiquitin-dependent kinase of MKK and IKK

Author

Listed:
  • Chen Wang

    (University of Texas Southwestern Medical Center)

  • Li Deng

    (University of Texas Southwestern Medical Center)

  • Mei Hong

    (University of Texas Southwestern Medical Center)

  • Giridhar R. Akkaraju

    (University of Texas Southwestern Medical Center)

  • Jun-ichiro Inoue

    (Keio University)

  • Zhijian J. Chen

    (University of Texas Southwestern Medical Center)

Abstract

TRAF6 is a signal transducer that activates IκB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS)1,2,3,4. IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism5. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism6,7. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13–Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK–p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.

Suggested Citation

  • Chen Wang & Li Deng & Mei Hong & Giridhar R. Akkaraju & Jun-ichiro Inoue & Zhijian J. Chen, 2001. "TAK1 is a ubiquitin-dependent kinase of MKK and IKK," Nature, Nature, vol. 412(6844), pages 346-351, July.
  • Handle: RePEc:nat:nature:v:412:y:2001:i:6844:d:10.1038_35085597
    DOI: 10.1038/35085597
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    Cited by:

    1. Cheng Peng & Yuanna Cheng & Mingtong Ma & Qiu Chen & Yongjia Duan & Shanshan Liu & Hongyu Cheng & Hua Yang & Jingping Huang & Wenyi Bu & Chenyue Shi & Xiangyang Wu & Jianxia Chen & Ruijuan Zheng & Zho, 2024. "Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Anirban Roy & Ashok Kumar, 2022. "Supraphysiological activation of TAK1 promotes skeletal muscle growth and mitigates neurogenic atrophy," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Yinan Yang & Huijing Zhou & Xiawei Huang & Chengfang Wu & Kewei Zheng & Jingrong Deng & Yonggang Zheng & Jiahui Wang & Xiaofeng Chi & Xianjue Ma & Huimin Pan & Rui Shen & Duojia Pan & Bo Liu, 2024. "Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Dongdong Wang & Yanxia Li & Hao Yang & Xiaoqi Shen & Xiaolin Shi & Chenyu Li & Yongjing Zhang & Xiaoyu Liu & Bin Jiang & Xudong Zhu & Hanwen Zhang & Xiaoyu Li & Hui Bai & Qing Yang & Wei Gao & Fang Ba, 2024. "Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Jingchun Du & Yougui Xiang & Hua Liu & Shuzhen Liu & Ashwani Kumar & Chao Xing & Zhigao Wang, 2021. "RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    6. Wenjun Xiong & Xueliang Gao & Tiantian Zhang & Baishan Jiang & Ming-Ming Hu & Xia Bu & Yang Gao & Lin-Zhou Zhang & Bo-Lin Xiao & Chuan He & Yishuang Sun & Haiou Li & Jie Shi & Xiangling Xiao & Bolin X, 2022. "USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Lingjie Yan & Tao Zhang & Kai Wang & Zezhao Chen & Yuanxin Yang & Bing Shan & Qi Sun & Mengmeng Zhang & Yichi Zhang & Yedan Zhong & Nan Liu & Jinyang Gu & Daichao Xu, 2022. "SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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