Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20.
Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20.
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DOI：
10.1007/s00018-011-0819-y
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发表时间：
2012-03
影响因子：
8
通讯作者：
Into, Takeshi
中科院分区：
文献类型：
--
作者：
Inomata, Megumi;Niida, Shumpei;Shibata, Ken-ichiro;Into, Takeshi
Toll样受体（TLR）信号传导与促进细胞内病原体消除的自噬有关。然而，自噬是否控制TLR信号传导在很大程度上是未知的。在这里，我们报告说，poly（I：C）刺激诱导TLR衔接分子TRIF和信号分子TRAF 6的选择性自噬降解，这是通过泛素编辑酶A20的基因沉默揭示的。这种类型的自噬诱导自噬体的形成，并且可以被自噬抑制剂和溶酶体抑制剂抑制。然而，这种自噬与典型的自噬过程无关，包括Beclin-1的参与和LC 3-I向LC 3-II的转化。通过在人类细胞中筛选TRIF相互作用的“自噬受体”，我们确定NDP 52介导TRIF和TRAF 6的选择性自噬降解，但不介导TRAF 3。NDP 52被TRAF 6多聚泛素化，并参与TRAF 6的聚集，这可能导致选择性降解。有趣的是，只有在A20沉默的条件下，NDP 52才能有效抑制poly（I：C）诱导的促炎基因表达。因此，本研究阐明了由在TRIF-TRAF 6下游起作用的NDP 52介导的选择性自噬机制。此外，尽管A20被认为是防止过度TLR信号传导的信号微调器，但矛盾的是，它下调了NDP 52对TLR信号传导的微调作用。本文的在线版本（doi：10.1007/s 00018 -011-0819-y）包含补充材料，可供授权用户使用。
Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly(I:C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin-editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting ‘autophagy receptors’ in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly(I:C)-induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF–TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling. The online version of this article (doi:10.1007/s00018-011-0819-y) contains supplementary material, which is available to authorized users.
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影响因子：
4.3
作者：
Matthias, Patrick;Yoshida, Minoru;Khochbin, Saadi
通讯作者：
Khochbin, Saadi
PELI1促进了TRIF依赖性Toll样受体信号传导和促炎性细胞因子的产生。
影响因子：
30.5
作者：
通讯作者：
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影响因子：
16
作者：
Kirkin, Vladimir;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
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DOI：
10.1083/jcb.130.1.1
发表时间：
1995-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Korioth F;Gieffers C;Maul GG;Frey J
通讯作者：
Frey J
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影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje