TRAF6-mediated degradation of DOK3 is required for production of IL-6 and TNFα in TLR9 signaling
TRAF6-mediated degradation of DOK3 is required for production of IL-6 and TNFα in TLR9 signaling
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TLR9 信号传导中产生 IL-6 和 TNFα 需要 TRAF6 介导的 DOK3 降解
DOI：
10.1016/j.molimm.2015.10.021
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发表时间：
2015-01-01
影响因子：
3.6
通讯作者：
Peng, Qisheng
中科院分区：
文献类型：
--
作者：
Liu, Ning;Tang, Bin;Peng, Qisheng
我们之前的研究表明，激酶 3 (DOK3) 的下游在 CpG 刺激巨噬细胞期间被降解。然而，Toll 样受体 9 (TLR9) 信号传导的潜在机制和作用仍然难以捉摸。在这项研究中，我们证明 CpG 处理通过与 E3 连接酶 TNFR 相关因子 6 (TRAF6) 相互作用，导致泛素介导的 DOK3 降解。我们还确定了 DOK3 的第 27 个氨基酸（赖氨酸）负责 DOK3 的 Ly48 多泛素化。此外，将 DOK3 (K27R) 重新引入 DOK3 缺陷型巨噬细胞可消除 CpG 诱导的 DOK3 降解，并抑制 IL-6 和 TNF α 的产生。更重要的是，我们的研究揭示了E3连接酶TRAF6的一个新作用，即TRAF6还能够催化目标蛋白除Lys 63多泛素化之外的Lys 48多泛素化。 (C) 2015 Elsevier Ltd. 保留所有权利。
Our previous study showed that the downstream of kinase 3 (DOK3) is degraded during macrophage stimulation with CpG. However, the underlying mechanism and role in Toll-like receptor 9 (TLR9) signaling remains elusive. In this study, we demonstrate that CpG treatment leads to ubiquitin-mediated degradation of DOK3 via interaction with an E3 ligase TNFR-associated factor 6 (TRAF6). We also identified the 27th amino acid (lysine) of DOK3 is responsible for Ly48 polyubiquitination of DOK3. Furthermore, reintroduction of DOK3 (K27R) into DOK3-deficient macrophages abolishes DOK3 degradation induced by CpG and suppresses the production of IL-6 and TNF alpha. More importantly, our study uncovers a novel role of an E3 ligase TRAF6, namely, TRAF6 is also able to catalyse Lys 48 polyubiquitylation of target protein except for Lys 63 polyubiquitylation. (C) 2015 Elsevier Ltd. All rights reserved.