Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation
Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation
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DOI：
10.1073/pnas.1014156108
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发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Srinivasula, Srinivasa M.
中科院分区：
文献类型：
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作者：
Fujita, Ken-ichi;Maeda, Daisuke;Srinivasula, Srinivasa M.
Toll样受体（TLR）通过调节自噬在几种先天免疫应答中起着至关重要的作用，但对TLR信号传导如何控制自噬知之甚少。在这里，我们证明了p62/SQSTM 1是TLR 4介导的自噬所必需的，我们将其显示为攻击样诱导结构（ALIS）的选择性自噬。用LPS或大肠杆菌处理诱导LC 3（+）点样结构，它们的组装，而不是溶酶体降解，独立于经典的自噬机制发生。显微镜和超微结构分析表明，p62是诱导的LC 3（+）点的组成部分，这些TLR 4诱导的p62（+）结构类似于ALIS。TLR 4激活的细胞中p62 mRNA和蛋白水平增加，p62敲低抑制ALIS形成和LC 3-II转化。p62和ALIS的积累需要通过活性氧-p38轴依赖性TLR 4/MyD 88信号转导激活Nrf 2，这表明先天免疫和氧化应激反应之间存在联系。这些结果表明，TLR 4驱动的p62的诱导在ALIS的形成和自噬降解中起着至关重要的作用，这可能是调节宿主防御的关键。
Toll-like receptors (TLRs) play a crucial role in several innate immune responses by regulating autophagy, but little is known about how TLR signaling controls autophagy. Here we demonstrate that p62/SQSTM1 is required for TLR4-mediated autophagy, which we show as selective autophagy of aggresome-like induced structures (ALIS). Treatment with LPS or Escherichia coli induced LC3(+) dot-like structures, and their assembly, but not lysosomal degradation, occurred independently of classic autophagic machinery. Microscopic and ultrastructural analyses showed that p62 is a component of the induced LC3(+) dots and these TLR4-induced p62(+) structures resemble ALIS. The levels of p62 mRNA and protein were increased in TLR4-activated cells and knockdown of p62 suppressed the ALIS formation and LC3-II conversion. The accumulation of p62 and ALIS required activation of Nrf2 by reactive oxygen species-p38 axis-dependent TLR4/MyD88 signaling, suggesting a link between innate immune and oxidative-stress responses. These findings indicate that TLR4-driven induction of p62 plays an essential role in the formation and the autophagic degradation of ALIS, which might be critical for regulating host defense.