Direct Activation of Protein Kinases by Unanchored Polyubiquitin Chains

By Zong-Ping Xia, Lijun Sun, Xiang Chen, Gabriel Pineda, Xiaomo Jiang, Anirban Adhikari, W. Zeng, Zhijian J. Chen. Nature, 2009

595 citations recorded by the source corpus.

TRAF6 is a ubiquitin ligase that is essential for the activation of NF-κB and MAP kinases in several signalling pathways, including those emanating from the interleukin 1 and Toll-like receptors. TRAF6 functions together with a ubiquitin-conjugating enzyme complex consisting of UBC13 (also known as UBE2N) and UEV1A (UBE2V1) to catalyse Lys 63-linked polyubiquitination, which activates the TAK1 (also known as MAP3K7) kinase complex. TAK1 in turn phosphorylates and activates IκB kinase (IKK), leading to the activation of NF-κB. Although several proteins are known to be polyubiquitinated in the IL1R and Toll-like receptor pathways, it is not clear whether ubiquitination of any of these proteins is important for TAK1 or IKK activation. By reconstituting TAK1 activation in vitro using purified proteins, here we show that free Lys 63 polyubiquitin chains, which are not conjugated to any target protein, directly activate TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2). This binding leads to autophosphorylation and activation of TAK1. Furthermore, we found that unanchored polyubiquitin chains synthesized by TRAF6 and UBCH5C (also known as UBE2D3) activate the IKK complex. Disassembly of the polyubiquitin chains by deubiquitination enzymes prevented TAK1 and IKK activation. These results indicate that unanchored polyubiquitin chains directly activate TAK1 and IKK, suggesting a new mechanism of protein kinase regulation.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/8506f605ffc22e5555511dc0cefd76d48c38f8a3

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In Cancer Research

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Citations in the corpus

• Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. (2012, background): “This complex is required for efficient activation by IL-1 and PAMPs of NF- B and, at least in some circumstances, JNK and p38 (140, 222, 304, 332) (FIGURE 6B).”
• Pattern recognition receptors and inflammation. (2010, background): “Together with an E2 ubiquitin-conjugating enzyme complex comprising Ubc13 and Uev1A, TRAF6 catalyzes the formation of a lysine 63 (K63)-linked polyubiquitin chain on TRAF6 itself as well as the generation of an unconjugated free polyubiquitin chain (Xia et al., 2009).”
• NF-κB, the first quarter-century: remarkable progress and outstanding questions. (2012, background): “This work suggested that unanchored ubiquitin chains might mediate kinase activation in cells (Xia et al. 2009).”
• RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. (2012, background): “Additionally, we show that RNF8 is highly active in making ubiquitin chains (Figure 1B), suggesting that RNF8 could catalyze free chains in proximity of the site of damage similarly to what happens with K63 ubiquitin chains during the NF-kB signaling (Xia et al., 2009).”
• Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, unknown): “Second, the activation of MAPK signal transduction requires cIAP-mediated TRAF6 and TAK1 translocation to the cytoplasm to promote TAB2/TAB3-dependent TAK1 oligomerization (94, 95).”
• Signaling in innate immunity and inflammation. (2012, background): “Both unanchored polyubiquitin formed by TRAF6 with the E2 UbcH5c (Xia et al. 2009) and linear polyubiquitin conjugated to IKKg (Rahighi et al.”